Montelukast

Bezeichnung:Montelukast

CAS-Nr158966-92-8

Englisch Name:Montelukast

CBNumberCB7112818

SummenformelC35H36ClNO3S

Molgewicht586.18

MOL-Datei158966-92-8.mol

Montelukast physikalisch-chemischer Eigenschaften

Schmelzpunkt	145-148 °C(Solv: toluene (108-88-3); methanol (67-56-1))
Siedepunkt	750.5±60.0 °C(Predicted)
Dichte	1.272±0.06 g/cm3(Predicted)
storage temp.	Store at 2-8°C
Löslichkeit	DMF: 2 mg/ml,DMSO: 2 mg/ml,Ethanol: insol,PBS (pH 7.2): insol
Aggregatzustand	A solid
pka	4.76±0.10(Predicted)
CAS Datenbank	158966-92-8(CAS DataBase Reference)
EPA chemische Informationen	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)

Sicherheit

Giftige Stoffe Daten

158966-92-8(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Montelukast Chemische Eigenschaften,Einsatz,Produktion Methoden

Originator
Singulair,Merck Pharmaceutical,Canada
Verwenden
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 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 cru
Trademarks
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.
Pharmakokinetik
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
Nebenwirkungen
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.
Stoffwechsel
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 Upstream-Materialien And Downstream Produkte

Montelukast Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

158966-92-8, Montelukast Verwandte Suche:

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