158966-92-8

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;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);Montelukast(Form A)
• CAS NO: 158966-92-8
• Molecular Formula: C₃₅H₃₆ClNO₃S
• Molecular Weight: 586.18
• EINECS: 256-723-9
• Mol File: 158966-92-8.mol

Chemical Properties

• Melting Point: 145-148 °C(Solv: toluene (108-88-3); methanol (67-56-1))
• Boiling Point: 750.45 °C at 760 mmHg
• Flash Point: 407.658 °C
• Appearance: /
• Density: 1.272 g/cm³
• Vapor Pressure: 1.17E-23mmHg at 25°C
• Refractive Index: 1.677
• PKA: 4.76±0.10(Predicted)
• CAS DataBase Reference: Montelukast(CAS DataBase Reference)
• NIST Chemistry Reference: Montelukast(158966-92-8)
• EPA Substance Registry System: Montelukast(158966-92-8)

Safety Data

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

Usage

Originator

Singulair,Merck Pharmaceutical,Canada

Uses

cardiostimulant,

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.

Drug interactions

Potentially hazardous interactions with other drugs None known

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.

InChI:InChI=1/C35H36ClNO3S/c1-34(2,40)30-9-4-3-7-25(30)13-17-32(41-23-35(18-19-35)22-33(38)39)27-8-5-6-24(20-27)10-15-29-16-12-26-11-14-28(36)21-31(26)37-29/h3-12,14-16,20-21,32,40H,13,17-19,22-23H2,1-2H3,(H,38,39)/t32-/m1/s1

Synthetic route

1-(mercaptomethyl)cyclopropane acetic acid disodium salt + C35H31ClNO5P → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 1-(mercaptomethyl)cyclopropane acetic acid disodium salt; C35H31ClNO5P With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -5 - 20℃; Inert atmosphere; Stage #2: With acetic acid In tetrahydrofuran at -5 - 0℃; pH=2 - 3;	98.7%

montransluconate p-aminoacetanilide → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In dichloromethane; water for 0.25h;	98.2%

[R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid (851755-56-1) + methylmagnesium chloride (676-58-4) → montelukast (158966-92-8)

Conditions	Yield
With cerium chloride In tetrahydrofuran at -5 - 65℃; for 3.5h; Inert atmosphere;	98%
With cerium(III) chloride In tetrahydrofuran at -5 - 65℃; Product distribution / selectivity; Inert atmosphere;	52.3%
In tetrahydrofuran; toluene at 0 - 5℃;
Stage #1: With cerium(III) chloride In tetrahydrofuran at -65 - 20℃; for 3h; Heating / reflux; Stage #2: methylmagnesium chloride In tetrahydrofuran at -5 - 0℃; for 3h; Stage #3: [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid With water; acetic acid Product distribution / selectivity; more than 3 stages;
Stage #1: methylmagnesium chloride With cerium(III) chloride In tetrahydrofuran at -5 - 0℃; Inert atmosphere; Stage #2: [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid In tetrahydrofuran at -5 - 0℃; Inert atmosphere;

(1-[(1(R)-(3-((E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(1-tetrahydropyran-2-yloxy-1-methylethyl)phenyl)propyl)thiomethyl]cyclopropyl)acetic acid adamantylamine salt (950665-85-7) → montelukast (158966-92-8)

Conditions	Yield
With hydrogenchloride In dichloromethane; water at 20℃; for 0.5h;	98%
With acetic acid Product distribution / selectivity;

1-(((1-(R)-(3-(2-(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic acid dipropylamine salt (880769-26-6) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In water; isopropyl alcohol at 4 - 40℃; for 17h; Reagent/catalyst; Temperature; Solvent; Inert atmosphere;	98%
With acetic acid In dichloromethane; water at 25 - 35℃; Product distribution / selectivity;	70.3%

2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester (152922-73-1) + 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol (807638-71-7) → montelukast (158966-92-8)

Conditions	Yield
With dmap In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere;	97.92%
Stage #1: 2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester; 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol With sodium methylate In dimethyl sulfoxide at -5 - 0℃; for 10h; Stage #2: With water; acetic acid at 10 - 20℃; pH=6.6; Product distribution / selectivity;
Stage #1: 2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester; 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol With sodium hydroxide In ISOPROPYLAMIDE; water at -6 - 38℃; Stage #2: With tartaric acid In tetrahydrofuran; water pH=3 - 5;

Montelukast sodium (151767-02-1) → montelukast (158966-92-8)

Conditions	Yield
With hydrogenchloride In water at 20 - 25℃; for 1h;	97%
With hydrogenchloride In water at 20℃; for 1h; pH=6;	97.9%
With hydrogenchloride; citric buffer In water; acetone at 20 - 25℃; for 2h;	76%

1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid L-(+)-α-phenylglycinol salt (1005743-16-7) → montelukast (158966-92-8)

Conditions	Yield
With water; acetic acid In toluene at 35℃; for 0.5h; pH=< 6; Product distribution / selectivity;	97%

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt (577953-88-9) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In water; isopropyl alcohol at 4 - 40℃; for 17h; Inert atmosphere;	97%
With acetic acid In water; toluene Product distribution / selectivity;	86.39%
With acetic acid In water; toluene Product distribution / selectivity;	86.39%

methyl magnesium iodide (917-64-6) + C39H34ClNO4S → montelukast (158966-92-8)

Conditions	Yield
Stage #1: methyl magnesium iodide With lanthanum(III) chloride; lithium chloride In toluene at 0℃; for 2h; Inert atmosphere; Stage #2: C39H34ClNO4S In tetrahydrofuran; toluene at 0℃; for 3h; Inert atmosphere;	94%

2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphatoxypropyl)phenyl)-2-propanol + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → montelukast (158966-92-8)

Conditions

Yield

Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With 3-ethyl-1-methyl-1H-imidazol-3-ium bromide In dimethyl sulfoxide at 10℃; for 0.0833333h; Stage #2: With potassium tert-butylate In dimethyl sulfoxide at 10℃; for 0.166667h; Stage #3: 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphatoxypropyl)phenyl)-2-propanol In dimethyl sulfoxide at 15 - 17℃; for 1h; Product distribution / selectivity;

93%

C36H36ClNO4S + methylmagnesium chloride (676-58-4) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: methylmagnesium chloride With zinc(II) chloride In tetrahydrofuran; 2-methyl-propan-1-ol at 5℃; for 0.666667h; Inert atmosphere; Stage #2: C36H36ClNO4S In tetrahydrofuran for 4h; Inert atmosphere;	92%

2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetonitrile (866923-62-8) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetonitrile With sodium hydroxide; ethanol; water for 15h; Heating / reflux; Stage #2: With acetic acid In ethanol; water; toluene Product distribution / selectivity;	91%
Stage #1: 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetonitrile With sodium hydroxide; ethanol; water for 30h; Heating / reflux; Stage #2: With water; acetic acid In toluene for 0.5h; pH=5.6; Product distribution / selectivity;	86%
Stage #1: 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetonitrile With sodium hydroxide; water; tetrabutylammomium bromide In toluene at 120℃; for 168h; Stage #2: With acetic acid In water; toluene Product distribution / selectivity;	83%

1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid methyl ester (855473-51-7) → montelukast (158966-92-8)

Conditions	Yield
With water; sodium hydroxide In tetrahydrofuran; methanol at 10 - 20℃; Product distribution / selectivity;	90.2%
With methanol; sodium hydroxide In tetrahydrofuran for 5h;	66%
Stage #1: 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid methyl ester With methanol; sodium hydroxide; water In tetrahydrofuran at 0 - 20℃; for 48h; Stage #2: With water; ammonium chloride; acetic acid In tetrahydrofuran pH=5; Product distribution / selectivity;	65.57%

sodium 1-(mercaptomethyl)-cyclopropane acetate (952585-15-8) + C36H34ClNO4S → montelukast (158966-92-8)

Conditions	Yield
at 10 - 20℃; for 10h; Concentration;	90.2%

C35H36ClNO3S*H3N (1124196-02-6) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In water at 25 - 30℃; for 5 - 6h; Product distribution / selectivity;	90%
With toluene at 50 - 60℃; for 6h; Product distribution / selectivity;

[R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(methylcarbonyl)phenyl] propyl]thio]methyl]cyclopropane acetic acid (937275-23-5) + methylmagnesium bromide (75-16-1) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: methylmagnesium bromide With lithium chloride In tetrahydrofuran at -10℃; for 0.5h; Inert atmosphere; Stage #2: [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(methylcarbonyl)phenyl] propyl]thio]methyl]cyclopropane acetic acid In tetrahydrofuran for 5h; Inert atmosphere;	90%

1-(mercaptomethyl)cyclopropanylacetic acid + 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol (1141487-07-1) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 1-(mercaptomethyl)cyclopropanylacetic acid; 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 18 - 20h; Stage #2: With ammonium chloride In water; N,N-dimethyl-formamide at 20℃; Product distribution / selectivity;	87.1%

(1-{1-(R)-(3-bromophenyl)-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid (1015076-80-8) + 7-chloro-2-ethenylquinoline (177748-00-4) → montelukast (158966-92-8)

Conditions	Yield
With triethylamine; palladium diacetate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 4.25h;	85%
With triethylamine; palladium diacetate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 4h; Product distribution / selectivity; Heck Reaction;	67.6%
Stage #1: (1-{1-(R)-(3-bromophenyl)-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid; 7-chloro-2-ethenylquinoline With triethylamine; palladium diacetate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 4h; Stage #2: With water; citric acid In ethyl acetate; N,N-dimethyl-formamide; toluene pH=3 - 4;
Stage #1: (1-{1-(R)-(3-bromophenyl)-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid; 7-chloro-2-ethenylquinoline; palladium diacetate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide for 0.25h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 100℃; for 4h; Stage #3: With citric acid In water; ethyl acetate; N,N-dimethyl-formamide; toluene pH=3 - 4;

C6H8N2*C35H36ClNO3S (1124196-05-9) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In toluene at 25 - 30℃; for 12 - 14h;	85%

C35H34ClNO4S + methylmagnesium bromide (75-16-1) → montelukast (158966-92-8)

Conditions	Yield
In toluene at -10 - -5℃; for 5h; Inert atmosphere;	85%

1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-((1-tetrahydropyranyloxy)-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropyl acetate (1000788-70-4) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-((1-tetrahydropyranyloxy)-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropyl acetate With pyridine; toluene-4-sulfonic acid In methanol at 60℃; for 8h; Stage #2: With sodium hydroxide In methanol at 30℃; for 2h;	84.9%

2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester (152922-73-1) + 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)-3-(methanesulfonyl-1-oxy)methylethyl)phenyl)-2-propanol (169954-93-2) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester With sodium hexamethyldisilazane In tetrahydrofuran at -15℃; for 1h; Inert atmosphere; Stage #2: 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)-3-(methanesulfonyl-1-oxy)methylethyl)phenyl)-2-propanol In tetrahydrofuran at -15℃; for 7h; Product distribution / selectivity; Inert atmosphere;	84.7%

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid benzylamine salt (1100021-03-1) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In toluene at 25 - 30℃; for 12 - 14h;	81%

C34H32ClNO4S*ClH → montelukast (158966-92-8)

Conditions	Yield
Stage #1: methylmagnesium chloride With cerium(III) chloride In tetrahydrofuran at 0 - 5℃; for 1.16667h; Stage #2: C34H32ClNO4S*ClH In tetrahydrofuran at 10℃; for 0.166667h; Stage #3: With water; sodium acetate; acetic acid In tetrahydrofuran Product distribution / selectivity;	80%

C34H32ClNO4S*ClH + methylmagnesium chloride (676-58-4) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: methylmagnesium chloride; cerium(III) chloride In tetrahydrofuran at 0 - 5℃; for 1.16667h; Stage #2: C34H32ClNO4S*ClH In tetrahydrofuran at 10℃; for 0.166667h;	80%

1-(mercaptomethyl)-cyclopropaneacetic acid (169954-92-1) + 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol (807638-71-7) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: 1-(mercaptomethyl)-cyclopropaneacetic acid; 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol With sodium hydroxide In N,N-dimethyl-formamide at -5 - 0℃; for 6h; Stage #2: With water; sodium chloride In Isopropyl acetate; N,N-dimethyl-formamide for 0.5h; Stage #3: With tartaric acid In water Product distribution / selectivity;	71.1%
Stage #1: 1-(mercaptomethyl)-cyclopropaneacetic acid; 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol With sodium hydroxide In N,N-dimethyl-formamide at -5 - 0℃; for 6h; Stage #2: With water; sodium chloride In Isopropyl acetate; N,N-dimethyl-formamide for 0.583333h; Stage #3: With tartaric acid In Isopropyl acetate; water at 0 - 20℃; for 4.25h; pH=4 - 5; Product distribution / selectivity;	42.54%
Stage #1: 1-(mercaptomethyl)-cyclopropaneacetic acid; 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol With sodium hydroxide In N,N-dimethyl-formamide at -5 - 0℃; for 6h; Stage #2: With water; sodium chloride In Isopropyl acetate; N,N-dimethyl-formamide for 0.75h; Stage #3: With pyrographite; tartaric acid Product distribution / selectivity; more than 3 stages;

montelukast isopropylamine salt (918972-53-9) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In dichloromethane; water at 25 - 35℃; for 0.5h;	70.3%
With acetic acid In dichloromethane; water at 25 - 35℃; for 0.5h; pH=4.5;	70.3%
With acetic acid In dichloromethane; water for 0.166667h; pH=4.0 - 4.5; Product distribution / selectivity;

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid α-methylbenzylamine salt (880769-29-9) → montelukast (158966-92-8)

Conditions	Yield
With acetic acid In dichloromethane; water at 20 - 25℃; Product distribution / selectivity; Heating / reflux;	70.3%

sodium hydroxide (1310-73-2) + montelukast (158966-92-8) → Montelukast sodium (151767-02-1)

Conditions	Yield
In methanol; toluene at 20℃; for 1h; Product distribution / selectivity;	100%
In methanol; toluene at 2 - 20℃; for 0.75h; Product distribution / selectivity;	100%
In methanol at 20℃; for 1h; Product distribution / selectivity;	73%
In methanol at 25 - 35℃; for 0.166667h;

montelukast (158966-92-8) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium hydroxide In methanol; toluene at 20℃; for 1h;	100%
With sodium hydroxide In methanol; water; toluene for 0.5h; Product distribution / selectivity; Alkaline aqueous solution;	98%
With sodium hydroxide In methanol at -5 - 35℃; for 1h;	98.7%

montelukast (158966-92-8) → C35H36ClNO3S*H3N (1124196-02-6)

Conditions	Yield
With ammonia In ethyl acetate at 20 - 25℃; for 1h;	97%

Cyclopentamine (1003-03-8) + montelukast (158966-92-8) → montelukast cyclopentylammonium (947373-22-0)

Conditions	Yield
In acetonitrile at 25℃; for 1h; Heating / reflux;	95%

cycloheptanamine (5452-35-7) + montelukast (158966-92-8) → (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid cycloheptylammonium salt (947370-32-3)

Conditions	Yield
In ethyl acetate at 25 - 60℃; for 1h;	95%
In ethyl acetate	65%
In ethyl acetate at 25℃; Product distribution / selectivity;
In ethyl acetate at 20℃;

Cyclododecylamine (1502-03-0) + montelukast (158966-92-8) → C12H25N*C35H36ClNO3S

Conditions	Yield
In cyclohexane; toluene at 25℃; for 1h; Heating / reflux;	95%

benzylamine (100-46-9) + montelukast (158966-92-8) → 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid benzylamine salt (1100021-03-1)

Conditions	Yield
In ethyl acetate at 20 - 25℃; for 1h;	95%
In n-heptane; ethyl acetate at 20 - 25℃; for 50h;
In ethyl acetate at 20℃; for 24h;

propylamine (107-10-8) + montelukast (158966-92-8) → montelukast n-propylamine salt (1100021-00-8)

Conditions	Yield
In n-heptane; toluene; acetonitrile	95%

2-aminobutanol (96-20-8, 13054-87-0) + montelukast (158966-92-8) → 1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropylacetate 2-amino-1-butanol

Conditions	Yield
In ethyl acetate at 15 - 25℃; for 5h; Time; Solvent; Temperature;	95%

cyclooctylamine (5452-37-9) + montelukast (158966-92-8) → (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid cyclooctylammonium salt (947370-34-5)

Conditions	Yield
In toluene at 25℃; for 1h; Heating / reflux;	94%
In ethyl acetate Product distribution / selectivity;	70%
In water; toluene for 1.5h; Product distribution / selectivity;	70%

N-cyclohexyl-cyclohexanamine (101-83-7) + montelukast (158966-92-8) → 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt (577953-88-9)

Conditions	Yield
In n-heptane; toluene Product distribution / selectivity;	90%
In ethyl acetate; toluene Product distribution / selectivity;	61%
In toluene at 20 - 25℃; for 0.25h; Product distribution / selectivity;	59.67%

Upstream product

• 851755-56-1 [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid 
• 676-58-4 methylmagnesium chloride 
• 807638-71-7 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol 
• 947370-34-5 (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid cyclooctylammonium salt 
• 855473-51-7 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid methyl ester 
• 1000788-71-5 2-[(1(R)-(3-((E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(1-(tetrahydropyran-2-yloxy)-1-methylethyl)phenyl)propyl)thiomethyl]-2-cyclopropylacetic acid 
• 866923-62-8 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetonitrile 
• 1005743-16-7 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid L-(+)-α-phenylglycinol salt 
• 918972-53-9 montelukast isopropylamine salt 
• 937275-23-5 [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(methylcarbonyl)phenyl] propyl]thio]methyl]cyclopropane acetic acid 
• 855473-47-1 2-((R)-3-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-methanesulfonyloxy-propyl)-benzoic acid methyl ester 
• 150026-72-5 -2-<3-<3-<2-(7-chloro-2-quinolinyl)ethenyl>phenyl>-3-hydroxypropyl>benzoic acid methyl ester 
• 577953-88-9 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt 
• 151767-02-1 Montelukast sodium 

Downstream Products

• 151767-02-1 Montelukast sodium 
• 1005743-12-3 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid tris(hydroxymethyl)aminomethane salt 
• 1005743-14-5 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid L-(+)-treo-2-amino-1-phenyl-1,3-propanediol salt 
• 1005743-16-7 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid L-(+)-α-phenylglycinol salt 
• 1008509-41-8 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid trans-4-aminocyclohexanol salt 
• 1008509-42-9 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid tert-octylamine salt 
• 1013023-55-6 montelukast morpholine salt 
• 577953-88-9 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt 
• 851755-58-3 montelukast tert-butylamine salt 
• 918972-54-0 [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-(1-methyl)ethenyl]phenyl]propyl]thio]methyl]cyclopropaneacetic acid 
• 945934-73-6 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid cyclohexylamine salt 
• 947373-22-0 montelukast cyclopentylammonium 
• 947370-32-3 (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid cycloheptylammonium salt 
• 950665-85-7 (1-[(1(R)-(3-((E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(1-tetrahydropyran-2-yloxy-1-methylethyl)phenyl)propyl)thiomethyl]cyclopropyl)acetic acid adamantylamine salt 

Relevant articles and documents

Montelukast sodium intermediate compound

The invention provides a novel montelukast sodium intermediate compound and a preparation method thereof. The intermediate compound is good in stability and convenient to store; the intermediate compound serves as a starting material of montelukast sodium, the synthesized montelukast sodium is high in yield and good in purity; and the structural formula of the intermediate compound is shown in thespecification,

Montelukast sodium intermediate and preparation method and application thereof

The invention relates to a series of novel compounds as shown in a formula (III) and a preparation method thereof. The invention also relates to an application of the novel compounds as shown in the formula (III) in synthesizing Montelukast sodium. The compounds as shown in the formula (III) are critical intermediates in the Montelukast sodium synthesizing process, and play a critical role of synthesizing the final target compound. The intermediate is stable in chemical property, the preparation process is mild in reaction condition, the yield is high, the optical purity is high, and the intermediate is suitable for large-scaled production. The formula is as shown in the description.

Production of montelukast

PROBLEM TO BE SOLVED: To provide a method of producing a montelukast with raw materials which are easy to handle and inexpensive and in simple reaction operations.SOLUTION: A method of producing a montelukast includes mixing a 1-(mercaptomethyl)cyclopropane acetic acid and an alcohol solution of a sodium methoxide and/or a sodium ethoxide in an aromatic hydrocarbon solvent, adding a reaction accelerator and then adding 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(methanesulfonyloxypropyl)phenyl)-2-propanol to the resultant disodium dianion solution to react them.

The crystal manufacturing method [...]

PROBLEM TO BE SOLVED: To provide a method for efficiently manufacturing dipropylamine 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methylcyclopropaneacetate by reacting dipropylamine with a crude form of 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methylcyclopropaneacetic acid.SOLUTION: When synthesizing dipropylamine 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methylcyclopropaneacetate, a solvent mixture of butyl acetate and a hydrocarbon having 5-7 carbon atoms is used as a solvent, and crystals are deposited from a solution.

Asymmetric Catalysis with Iron-Salen Complexes

Iron(III)-salen complexes based on a chiral cis-2,5-diaminobicyclo[2.2.2]octane scaffold are used as catalysts for a variety of stereo selective reactions. High enantio- and diastereoselectivities can be achieved with these catalysts in sulfa-Michael conjugate addition to acyclic α,β-unsaturated ketones, in regioselective δ-addition of thiols to acyclic α,β,γ,δ-unsaturated ketones, and in Conia-ene carbocyclization of alkynyl-substituted β-dicarbonyl compounds. The use of these chiral iron-salen complexes as catalysts provides a new method for conducting these three important reactions under environmentally sustainable conditions.

Preparation method of montelukast

The invention discloses a preparation method of montelukast. An inorganic base solution is cooled to 0-10 DEG C, 1-(mercaptomethyl)-cyclopropaneacetic acid is added, and a stirred reaction is performed to obtain a 1-(mercaptomethyl)-cyclopropaneacetic acid dianion base solution; a quinolinediol compound is dissolved into water, and inorganic base and a phase transfer catalyst are added for stirring and even mixing; after the mixture is cooled to 0-10 DEG C, paratoluensulfonyl chloride is added for a reaction to obtain a tosylate compound solution, and then the tosylate compound solution is added into the 1-(mercaptomethyl)-cyclopropaneacetic acid dianion base solution for a stirred reaction to obtain a water solution of montelukast; then the montelukast solid is obtained through post-treatment. The method is simple in technology, mild in reaction condition, economical, environmentally friendly and high in yield and makes industrialized production easy.

Preparation method of montelukast sodium intermediates

The invention relates to a preparation method of montelukast sodium intermediates. The method comprises the steps that under the protection of inert gas, in solvent, nucleophilic substitution is conducted on a montelukast mother nucleus compound, replaced by various leaving groups, of secondary hydroxyl and various side chains respectively under the action of a catalyst, and various montelukast sodium intermediates are obtained. According to the preparation method of the montelukast sodium intermediates, new catalysts of 4-dimethylaminopyridine and 4-pyrrolidinopyridine are utilized, the reaction is mild in condition and rapid, the product is single, purification is easy and convenient, the obtained intermediates are high in optical purity and higher in yield, and the preparation method is more suitable for industrial production.

And Menlust sodium process for the preparation of intermediates

The invention relates to a method suitable for preparing montelukast sodium and intermediate 2-(3(S)-(3-(2-(7-chlorine-2-quinolyl) vinyl) phenyl)-3-hydroxypropyl) phenyl)-2-propoxy) tetrahydropyrane (intermediate 3) of the montelukast sodium in a large scale. According to the method, 7-chloroquinaldine and 3-cyanobenzaldehyde are used as starting raw materials, 2-(3-(3-(2-(7-chlorine-2-quinolyl) vinyl) phenyl)-3-oxopropyl) phenyl)-2-propoxy) tetrahydropyrane (intermediate 2) is obtained by six steps of reaction, then intermediate 3 with ee more than 99% and yield more than 90% is obtained by chiral reduction, and the montelukast sodium with high optical purity and high chemical purity is obtained by the intermediate 3 through four steps of reaction.

Method for preparing montelukast sodium from montelukast acid

The invention discloses a preparation method of montelukast sodium. The preparation method comprises: converting a montelukast acid crude product into a montelukast acid p-amino acetanilide salt, specifically, dissolving the montelukast acid crude product in an acetone/n-hexane mixture, adding p-amino acetanilide, stirring for reaction for 7-10 hours at 15-30 DEG C, then adding cyclohexane which accounts for 1/4 of the total volume of the acetone/cyclohexane mixture, stirring for reaction for 2 hours at 20 DEG C, and carrying out filtration and drying to obtain the montelukast acid p-amino acetanilide salt, wherein the mole ratio of montelukast acid to p-amino acetanilide is 1:1.5-2.0; recrystallizing to refine the amine salt; acidifying the refined amine salt, and carrying out dissociation to obtain high-purity montelukast acid; and converting the montelukast acid into montelukast sodium. The preparation method of montelukast sodium disclosed by the invention is simple in process, high in yield and good in impurity removal effect, the purity of the prepared montelukast sodium is more than 99.9%, and the content of styrene and sulfoxide impurities is lower than 0.02%.

METHOD FOR PRODUCING CRYSTAL OF MONTELUKAST FREE ACID

PROBLEM TO BE SOLVED: To provide a method for producing high-purity 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (montelukast free acid) efficiently in high yield. SOLUTION: The method for producing high-purity montelukast free acid, in which acid salt of organic amine salt does not remain, efficiently in high yield comprises a step of continuously performing such a reaction that montelukast organic amine salt is led to the montelukast free acid by using an acid in a mixture of a water-soluble organic solvent with water and continuously crystallizing the montelukast free acid from the obtained reaction solution. COPYRIGHT: (C)2015,JPO&INPIT