Montelukast CAS 158966-92-8

Introduction：Basic information about Montelukast CAS 158966-92-8, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Montelukast Basic information

• Product Name: Montelukast
• Synonyms: (r-(e))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid;2-[1-[[(1r)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid;Montelukas;Montelukast;Montelukast Acid;Montelukast(Form A);Cyclopropaneaceticacid,1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-Methylethyl)phenyl]propyl]thio]Methyl]-;Montelukast D6 sodium salt (Rac)
• CAS: 158966-92-8
• MF: C35H36ClNO3S
• MW: 586.18
• EINECS: 256-723-9
• Product Categories: 158966-92-8
• Mol File: 158966-92-8.mol

Montelukast Chemical Properties

• Melting point: 145-148 °C(Solv: toluene (108-88-3); methanol (67-56-1))
• Boiling point: 750.5±60.0 °C(Predicted)
• density: 1.272±0.06 g/cm3(Predicted)
• storage temp.: Store at 2-8°C
• solubility: DMF: 2 mg/ml,DMSO: 2 mg/ml,Ethanol: insol,PBS (pH 7.2): insol
• pka: 4.76±0.10(Predicted)
• form: A solid
• color: Light yellow to yellow
• InChIKey: UCHDWCPVSPXUMX-TZIWLTJVSA-N
• SMILES: C1(CS[C@@H](C2=CC=CC(/C=C/C3C=CC4C(N=3)=CC(Cl)=CC=4)=C2)CCC2=CC=CC=C2C(O)(C)C)(CC(O)=O)CC1
• CAS DataBase Reference: 158966-92-8(CAS DataBase Reference)
• EPA Substance Registry System: Cyclopropaneacetic acid, 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]- (158966-92-8)

Safety Information

• Hazardous Substances Data: 158966-92-8(Hazardous Substances Data)

Montelukast Usage And Synthesis

Originator

Singulair,Merck Pharmaceutical,Canada

Uses

cardiostimulant,

Definition

ChEBI: Montelukast is a member of quinolines, a monocarboxylic acid and an aliphatic sulfide. It has a role as a leukotriene antagonist, an anti-asthmatic drug and an anti-arrhythmia drug. It is a conjugate acid of a montelukast(1-).

Manufacturing Process

Crotonaldehyde (3.23 mol) in 100 mL of 2-butanol was added dropwise to arefluxing solution of 4-chloroaniline (3.23 mol), p-chloranil (3.23 mol) and HClconc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solventwas removed under vacuum at 60°C. Then 2 L of toluene was added to thereaction mixture followed by removal of 2.5-3 L of solvent until a very pastysolid formed. THF (2 L) was added and the mixture heated 30 min after whichit was cooled to 0°C. The solid was collected and washed with THF until pureby tlc. The solid was then dissolved in aq. K2CO3/EtOAc and the organic phaseseparated. The aqueous phase was extracted with EtOAc and the organicphases combined, dried over MgSO4 and the solvent removed. The productwas crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of4-chloro-2-methylquinolin.
4-Chloro-2-methylquinalin was converted into 3-(2-(7-chloro)-2-quinolinyl)ethenyl)benzaldehyde. Reaction was carried out according to amethod 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 vinylmagnesiumbromide in toluene/THF (370 mL). After stirring for 1 hour at 0°C, thereaction was quenched by the addition of saturated NH4Cl solution (150 ml),followed by H2O (500 mL) and HOAc (50 mL). The product was extracted withEtOAc and the two-phase system was filtered through celite to remove aninsoluble precipitate. The aqueous phase was then re-extracted with EtOAc(100 mL) and the combined organic layer was washed with H2O, followed bybrine. The solution was dried (MgSO4), and evaporated to give a dark yellowresidue which was purified by flash chromatography (EtOAc:hexane 1:5, then1:3). 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 wasrecrystallized 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 inDMF (90 mL) was stirred for 2 hours at 100°C. The dark red solution was thencooled to 0°C and poured into saturated NaHCO3 solution (500 mL). Theproduct was extracted with EtOAc and the organic layer was washed with H2Ofollowed by brine. The solvent was removed under vacuum and the residuewas purified by flash chromatography (EtOAc:hexane 1:10, 1:5 and 3:10) togive 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 refluxedovernight using a Dean Stark trap filled with activated molecular sieves.Methyl magnesium chloride (3.0 Molar solution in THF, 790 mmol) was addeddropwise over 30 min to the CeCl3 slurry at 0°C. After stirring 2 hours, themixture 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 stirredanother hour before the addition of 2 M HOAc (600 mL) and toluene (600mL). The organic layer was washed with saturated aq. NaHCO3 and with brine.Concentration in vacuo and purification of the residue by flashchromatography (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 washeated at reflux for 6 hours, cooled to r.t., and MeOH (300 mL) was cautiouslyadded. 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) andSOCl2 (15.9 g, 134 mmol) was added dropwise over a period of 15 min at25°C. After stirring for another 15 min, the mixture was washed with aqueousNaHCO3. The organic extract was dried over Na2SO4, filtered and concentratedto give quantitatively the 1,1-cyclopropanedimethanol cyclic sulfite.
To a solution of the 1,1-cyclopropanedimethanol cyclic sulfite (99 mmol) inDMF (83 mL) was added NaCN (199 mmol). The mixture was heated to 90°Cfor 20 hours. Upon cooling, EtOAc (400 mL) was added and the solution waswashed with saturated NaHCO3 solution (55 mL), H2O (4 times 55 mL),saturated NaCl solution and dried over Na2SO4. The solution was concentratedto 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 byCH3SO2Cl (562 mmol) dropwise. The mixture was warmed to 25°C, washedwith NaHCO3, dried over Na2SO4 and concentrated in vacuo to give thecorresponding mesylate. The mesylate was then dissolved in DMF (450 mL)and cooled to 0°C. Potassium thioacetate (55.4 g, 485 mmol) was added, andthe mixture was stirred at 25°C for 18 hours. EtOAc (1.5 L) was added, thesolution was washed with NaHCO3, dried over Na2SO4 and concentrated invacuo 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). Themixture was heated to reflux for 20 hours, cooled to 25°C, H2O (1 L) wasadded and the product was extracted with CH2Cl2. The organic extract waswashed with H2O and dried over Na2SO4. Concentration of the organic solutiongave 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) andDMF (1 mL) at -40°C was added diisopropylethylamine (2.2 mmol) and thenmethanesulfonyl chloride (2.2 mmol). The mixture was stirred 2 hours withslow warming to -30°C. The methyl 1-(thiomethyl)cyclopropaneacetate (2.3mmol) was added to the cloudy reaction mixture followed by dropwiseaddition of potassium tert-butoxide/THF solution (4.4 mmol). The reactionmixture was stirred at -30°C for 3.5 hours before quenching it with 25% aqNH4OAc. Extraction with EtOAc, washing the organic layer with brine andevaporation of the solvents left a residue that was purified by flashchromatography (5%-10% EtOAc in toluene) giving 658 mg (53%) of methyl1-((((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 name

Singulair (Merck).

Therapeutic Function

Anti-asthmatic

Mechanism of action

Montelukast 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.

Pharmacokinetics

Montelukast 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.

Clinical Use

Leukotriene receptor antagonist:
Prophylaxis of asthma
Seasonal allergic rhinitis

Side effects

Montelukast 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.

Metabolism

Extensively metabolised in the liver by cytochrome P450 isoenzymes CYP3A4, CYP2A6, and CYP2C9.Excreted principally in the faeces via the bile. Metabolites have minimal therapeutic activity.

Montelukast Preparation Products And Raw materials

• Raw materials: Sodium chloride-->Diethylamine-->Silica gel-->Ammonium acetate-->tert-Butyldimethylsilyl chloride-->Vinyl bromide-->Sodium cyanide-->methyl 2-(2-iodophenyl)propanoate-->Methanesulfonyl chloride-->Crotonaldehyde (trans predominantly)-->Vinylmagnesium bromide-->Methylmagnesium chloride-->Borane-tetrahydrofuran complex-->CERIUM(III) CHLORIDE-->Diethyl 1,1-cyclopropanedicarboxylate-->Thionyl chloride-->Chloranil-->4-Chloroaniline-->Tetrabutyl ammonium chloride-->Palladium (II) Acetate-->Potassium tert-butoxide-->N,N-Diisopropylethylamine-->Triethylamine