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Montelukast Basic information
Montelukast Chemical Properties
Safety Information
Montelukast Usage And Synthesis
  • OriginatorSingulair,Merck Pharmaceutical,Canada
  • Usescardiostimulant,
  • Manufacturing ProcessCrotonaldehyde (3.23 mol) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 4-chloroaniline (3.23 mol), p-chloranil (3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at 60°C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2 L) was added and the mixture heated 30 min after which it was cooled to 0°C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2CO3/EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc and the organic phases combined, dried over MgSO4 and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of 4-chloro-2-methylquinolin.
    4-Chloro-2-methylquinalin was converted into 3-(2-(7-chloro)-2- quinolinyl)ethenyl)benzaldehyde. Reaction was carried out according to a method described in U.S. Pat. No. 4,851,409
    To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (0.34 mol) in toluene (700 mL) at 0°C was added 1.0 M vinylmagnesium bromide in toluene/THF (370 mL). After stirring for 1 hour at 0°C, the reaction was quenched by the addition of saturated NH4Cl solution (150 ml), followed by H2O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a solid of 1- (3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol (melting point = 110-112°C). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g.
    A degassed suspension of 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol (46.6 mmol), n-Bu4NCl (93 mmol), LiOAcH2O (115 mmol), LiCl (93 mmol), Pd(OAc)2 (1.4 mmol) and methyl 2-(2-iodophenyl)propanoate in DMF (90 mL) was stirred for 2 hours at 100°C. The dark red solution was then cooled to 0°C and poured into saturated NaHCO3 solution (500 mL). The product was extracted with EtOAc and the organic layer was washed with H2O followed by brine. The solvent was removed under vacuum and the residue was purified by flash chromatography (EtOAc:hexane 1:10, 1:5 and 3:10) to give a pale yellow foam of ethyl 2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-hydroxy-propyl)benzoate (18.9 g).
    A mixture of anhydrous CeCl3 (164 mmol) in THF (500 mL) was refluxed overnight using a Dean Stark trap filled with activated molecular sieves. Methyl magnesium chloride (3.0 Molar solution in THF, 790 mmol) was added dropwise over 30 min to the CeCl3 slurry at 0°C. After stirring 2 hours, the mixture was cooled to -5°C and a toluene (600 mL) solution of the ethyl 2- (3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxy-propyl)benzoate (152 mmol) was added dropwise over 1 hour. The reaction mixture was stirred another hour before the addition of 2 M HOAc (600 mL) and toluene (600 mL). The organic layer was washed with saturated aq. NaHCO3 and with brine. Concentration in vacuo and purification of the residue by flash chromatography (30% EtOAc in toluene) gave 63.48 g (91%) of the 2-(2- (3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2- propanol.
    To a solution of BH3THF complex (1 M in THF, 262 mL) was added diethyl 1,1- cyclopropanedicarboxylate (134 mmol) at 25°C under N2. The solution was heated at reflux for 6 hours, cooled to r.t., and MeOH (300 mL) was cautiously added. The solution was stirred for 1 hour and then concentrated to an oil. The crude 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3- hydroxypropyl)phenyl)-2-propanol was dissolved in CH2Cl2 (234 mL) and SOCl2 (15.9 g, 134 mmol) was added dropwise over a period of 15 min at 25°C. After stirring for another 15 min, the mixture was washed with aqueous NaHCO3. The organic extract was dried over Na2SO4, filtered and concentrated to give quantitatively the 1,1-cyclopropanedimethanol cyclic sulfite.
    To a solution of the 1,1-cyclopropanedimethanol cyclic sulfite (99 mmol) in DMF (83 mL) was added NaCN (199 mmol). The mixture was heated to 90°C for 20 hours. Upon cooling, EtOAc (400 mL) was added and the solution was washed with saturated NaHCO3 solution (55 mL), H2O (4 times 55 mL), saturated NaCl solution and dried over Na2SO4. The solution was concentrated to give 7.1 g (65%) of 1-(hydroxymethyl)cyclopropaneacetonitrile.
    To a solution of 1-(hydroxymethyl)cyclopropaneacetonitrile (42 g, 378 mmol) in dry CH2Cl2 (450 mL) at -30°C was added Et3N (741 mmol) followed by CH3SO2Cl (562 mmol) dropwise. The mixture was warmed to 25°C, washed with NaHCO3, dried over Na2SO4 and concentrated in vacuo to give the corresponding mesylate. The mesylate was then dissolved in DMF (450 mL) and cooled to 0°C. Potassium thioacetate (55.4 g, 485 mmol) was added, and the mixture was stirred at 25°C for 18 hours. EtOAc (1.5 L) was added, the solution was washed with NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 45 g (70%) of 1-(acetythiomethyl)cyclopropaneacetonitrile.
    To a solution of the 1-(acetythiomethyl)cyclopropaneacetonitrile (266 mmol) in MeOH (1.36 L) was added H2O (84 mL) and conc. H2SO4(168 mL). The mixture was heated to reflux for 20 hours, cooled to 25°C, H2O (1 L) was added and the product was extracted with CH2Cl2. The organic extract was washed with H2O and dried over Na2SO4. Concentration of the organic solution gave 36 g (93%) of the methyl 1-(thiomethyl)cyclopropaneacetate.
    To a solution of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3- hydroxypropyl)phenyl)-2-propanol in THF was dissolved in THF (1 mL) and DMF (1 mL) at -40°C was added diisopropylethylamine (2.2 mmol) and then methanesulfonyl chloride (2.2 mmol). The mixture was stirred 2 hours with slow warming to -30°C. The methyl 1-(thiomethyl)cyclopropaneacetate (2.3 mmol) was added to the cloudy reaction mixture followed by dropwise addition of potassium tert-butoxide/THF solution (4.4 mmol). The reaction mixture was stirred at -30°C for 3.5 hours before quenching it with 25% aq NH4OAc. Extraction with EtOAc, washing the organic layer with brine and evaporation of the solvents left a residue that was purified by flash chromatography (5%-10% EtOAc in toluene) giving 658 mg (53%) of methyl 1-((((R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2- propyl)phenyl)propyl)thio)methyl)cyclopropaneacetate.
    Following the hydrolysis the methyl 1-((((R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetate with NaOH was obtained the free acid: 4-((1(R)-(3-(2-(7- chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)propyl) thio)methyl)cyclopropaneacetic acid or sodium 1-(((1(R)-(3-(2-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio) methyl) cyclopropaneacetate.
  • brand nameSingulair (Merck).
  • Therapeutic FunctionAnti-asthmatic
  • Mechanism of actionMontelukast was developed from other weakly antagonistic quinoline derivatives. A number of changes can be made to the structure without the loss of activity. These include changing the double bond between the two aromatic rings to an ether linkage, reducing the quinoline ring, changing the chlorine to a fluorine, and/or exchanging the sulfur for an amide group.
  • PharmacokineticsMontelukast is a high-affinity, selective antagonist of the cysLT1 receptor. It is rapidly absorbed orally, with a bioavailability of 64%. Montelukast is 99% bound to plasma proteins and is extensively metabolized in the liver by CYP3A4 and CYP2C9 to oxidated products. CYP3A4 oxidizes the sulfur and the C-21 benzylic carbon, whereas CYP2C9 is selectively responsible for the methyl hydroxylation.
  • Side effectsMontelukast did not demonstrate any significant adverse effects greater than placebo in clinical trials; however, because it is metabolized by the cytochrome P450 (CYP450) enzymes, its plasma levels should be monitored when coadministered with CYP450-inducing drugs, such as phenobarbital, rifampin, and phenytoin.
Montelukast Preparation Products And Raw materials
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