151767-02-1

Basic information

• Product Name: Montelukast sodium
• Synonyms: singulair;MONTELUKAST NA;MONTELUKAST SODIUM;mk-476;2-[1-[[1-[3-[2-[(7-chloro-2-quinolyl)]vinyl]phenyl]-3-[2-(1-hydroxy-1-methyl-ethyl)phenyl]-propyl]sulfanylmethyl]cyclopropyl]acetic acid sodium salt;1-[1-[[[(1R)-1-[3-[(1E)-2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic;MK-476, Singulair;Montelukast, Sodium Salt
• CAS NO: 151767-02-1
• Molecular Formula: C₃₅H₃₅ClNO₃S*Na
• Molecular Weight: 608.17
• EINECS: 1308068-626-2
• Product Categories: Active Pharmaceutical Ingredients;APIs;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Isotope Labeled Compounds;Pharmaceutical intermediates;DIOXYLINE;Other APIs;Inhibitors
• Mol File: 151767-02-1.mol

Chemical Properties

• Melting Point: 115 °C(dec.)
• Boiling Point: 750.5 °C at 760 mmHg
• Flash Point: 407.7 °C
• Appearance: white to tan/
• Storage Temp.: -20°C Freezer, Under Inert Atmosphere
• Solubility: DMSO: ≥8mg/mL at 60°C
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO, distilled water, or ethanol may be stored at -20°C for up to 1 month.
• Merck: 14,6258
• CAS DataBase Reference: Montelukast sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Montelukast sodium(151767-02-1)
• EPA Substance Registry System: Montelukast sodium(151767-02-1)

Safety Data

• Hazard Codes: Xi
• Statements: 63-41-62
• Safety Statements: 26
• WGK Germany: 3
• RTECS: GZ0698000
• Hazardous Substances Data: 151767-02-1(Hazardous Substances Data)

Usage

Uses

Used in Asthma Treatment:
Montelukast sodium is used as an antiasthmatic agent for patients with mild to moderate asthma that is not adequately controlled by inhaled corticosteroids and short-acting beta2-agonists. It acts as a selective leukotriene D4-receptor antagonist, blocking the effects of cysteinyl leukotrienes LTC4, LTD4, and LTE4 on microvascular permeability and the activation of eosinophils.
Used in Allergic Rhinitis:
Montelukast sodium is used to alleviate the symptoms caused by allergic rhinitis, providing relief from nasal congestion, sneezing, and itching.
Used in Antifungal Applications:
Montelukast sodium is used as an anti-infective agent, potentially offering a new approach to combat fungal infections.
Used in Drug Delivery Systems:
Montelukast sodium hydrate has been used as a positive control drug to study the protective effects of Gumiganghwal-tang aqueous extract (GGTA) against airway inflammation and pulmonary fibrosis, indicating its potential use in drug delivery systems for targeted treatment.
Used in Pharmaceutical Research:
As a potent and highly selective CysLT1 receptor antagonist without demonstrated CysLT2 activity, Montelukast sodium is a valuable compound for pharmaceutical research and development, particularly in the areas of asthma and allergic rhinitis treatment.
Brand Name:
Singulair (Merck) is the brand name under which Montelukast sodium is marketed, making it widely accessible to patients in need of asthma and allergic rhinitis treatment.

Pharmacological effect

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) is a eicosane-type substance released by various kinds of cells including mast cells and eosinophils with strong inflammatory effect. These important asthma pre-inflammatory mediators can bind to the Cysteinyl leukotriene receptors (CysLT) identified in the human airways, resulting in a variety of airway responses including bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil accumulation. Montelukast sodium is an orally active selective leukotriene receptor antagonist that can specifically inhibit the cysteinyl leukotriene receptor. It was successfully developed by the Merck Company (German) and had entered into market in Canada, Finland, and Mexican in 1997. It is suitable for the prevention and long-term treatment of adults and children asthma, including the prevention of daytime and nighttime asthma symptoms, the treatment of asthma patients who are aspirin-sensitive and prevention of exercise-induced bronchial contraction, it can also be used to relieve the seasonal allergic rhinitis symptoms of 15 year-old or over 15 year-old patients whose symptoms are invalid and intolerant to other treatment. Montelukast is a selective leukotriene receptor antagonist and has been approved for the oral administration treatment of asthma and allergic rhinitis. It is also a potent oral preparation that can significantly improve the inflammatory indicators. Biological determination of biochemistry and pharmacology has showed that montelukast sodium has a high affinity and selectivity to the CysLT1 receptors (compared with other kinds of pharmacologically important airway receptors such as prostanoid, cholinergic and β-adrenergic receptors). Montelukast can effectively suppress the physiological effects caused by the binding between LTC4, LTD4 and LTE4 receptor and CysLT1 receptor without any receptor agonistic activity. There is the secondary type of cysteinyl leukotriene receptor (CysLT2) presented in the lungs cysteinyl leukotriene receptor but may be limited to the blood vessels. So far, researchers haven’t cloned two receptors so the situation of CysLT receptor is illustrated through binding assay and pharmacological analysis. It has been now thought that montelukast does not antagonize CysLT2 receptors. The above information is edited by the lookchem of Dai Xiongfeng.

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. 4,851,409To 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.

Therapeutic Function

Anti-asthmatic

Biochem/physiol Actions

Montelukast sodium hydrate is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is a subtype specific CysLT1 receptor antagonist.

References

1) Lynch?et al.?(1999),?Characterization of the human cysteinyl leukotriene CysLT1 receptor; Nature,?399?789 2) Jones?et al. (1995),?Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist; Can. J. Physiol. Pharmacol.,?73?191 3) Reiss?et al.?(1998),?Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group; Arch. Intern. Med.,?158?1213 4) Zhao?et al.?(2011),?Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats; J. Pharm. Pharmacol.,?63?550 5) Lenz?et al.?(2014),?Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood-brain barrier dysfunction; Neuroscience,?277?859 6) Huber?et al.?(2011)?Inhibition of leukotriene receptors boosts neural progenitor proliferation; Cell Physiol. Biochem.,?28?793

InChI:InChI=1/C35H36ClNO3S.Na/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);/q;+1/p-1/b15-10+;

Synthetic route

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%

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 sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 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 With acetic acid In dichloromethane; water pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 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 With acetic acid In water; toluene at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With sodium hydroxide In methanol at 20 - 25℃; for 2h; Inert atmosphere;	94%

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 sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 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 With acetic acid In dichloromethane; water pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 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 With acetic acid In dichloromethane; water at 25 - 35℃; for 0.75h; Stage #2: With sodium hydroxide In ethanol; dichloromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	75.6%
Stage #1: 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 With acetic acid In dichloromethane; water at 25 - 35℃; Stage #2: With sodium hydroxide In ethanol at 25 - 30℃; Product distribution / selectivity;	75.6%

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 sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With acetic acid In dichloromethane; water pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 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 With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-chloro benzylamine salt (1254938-23-2) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-chloro benzylamine salt With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-chloro benzylamine salt With acetic acid In dichloromethane; water pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-methoxy benzylamine salt → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-methoxy benzylamine salt With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-methoxy benzylamine salt With acetic acid In dichloromethane; water pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	99%

sodium hydroxide (1310-73-2) + 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 sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With water; acetic acid In toluene at 20 - 25℃; for 0.166667h; Stage #2: sodium hydroxide In ethanol; water; toluene at 20℃; for 0.333333h;	98%

1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-bromo benzylamine salt (1254938-26-5) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-bromo benzylamine salt With acetic acid In dichloromethane pH=4 - 4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	98%
Stage #1: 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-bromo benzylamine salt With acetic acid In dichloromethane; water pH=4.5; Stage #2: With pyrographite; sodium hydroxide In methanol; water for 1h;	98%

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 → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With acetic acid In dichloromethane; water for 0.25h; Stage #2: With pyrographite; sodium sulfate; sodium hydroxide In methanol at 15 - 25℃; for 1h; Temperature;	97.2%

montelukast isopropylamine salt (918972-53-9) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium t-butanolate In toluene at 30 - 35℃; for 0.75h; Product distribution / selectivity; Inert atmosphere; Darkness;	94%
With sodium t-butanolate In toluene at 35℃;	78%
Stage #1: montelukast isopropylamine salt With hydrogenchloride In dichloromethane; water at 10 - 25℃; for 0.5h; pH=4 - 4.5; Stage #2: With sodium hydroxide In ethanol; dichloromethane at 8 - 12℃; for 2h;
Stage #1: montelukast isopropylamine salt With hydrogenchloride In dichloromethane; water at 10 - 20℃; pH=4 - 4.5; Inert atmosphere; Stage #2: With sodium hydroxide In ethanol; dichloromethane at 8 - 12℃; for 30h; Inert atmosphere;

1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid R-(+)-α-methylbenzylamine salt → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium methylate; pyrographite In toluene at 25 - 30℃; for 1.5h;	93%

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 sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With acetic acid In water; isopropyl alcohol at 4 - 40℃; for 17h; Inert atmosphere; Stage #2: With sodium hydroxide In methanol for 1h;	92%
Stage #1: 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 With acetic acid In dichloromethane; water at 25 - 30℃; for 0.75h; Stage #2: With sodium hydroxide In ethanol; dichloromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	67.8%
Stage #1: 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 With acetic acid In dichloromethane; water at 25 - 35℃; Stage #2: With sodium hydroxide In ethanol at 25 - 30℃; Product distribution / selectivity;	67.8%

cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate (142522-28-9) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 0.5h; Inert atmosphere;	92%

montelukast N-methyl-morpholine salt (942303-96-0) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium methylate In toluene at 25 - 30℃; for 0.5h;	90%

montelukast hexamethylenediamine → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: montelukast hexamethylenediamine With tartaric acid In dichloromethane; water for 0.25 - 0.333333h; Stage #2: With sodium hydroxide In methanol; dichloromethane for 0.0833333 - 0.166667h;	90%

(R,E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)-phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)-methyl)cyclopropyl)acetic acid L-(-)-ephedrine → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: (R,E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)-phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)-methyl)cyclopropyl)acetic acid L-(-)-ephedrine With acetic acid In dichloromethane; water pH=7; Inert atmosphere; Stage #2: With sodium hydroxide In methanol for 1h; Activated carbon;	86.8%

Montelukast L-ephedrine salt (1312993-47-7) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: Montelukast L-ephedrine salt With acetic acid In dichloromethane; water at 15 - 20℃; pH=7; Inert atmosphere; Stage #2: With sodium hydroxide In methanol at 32℃;	86.8%

montelukast n-propylamine salt (1100021-00-8) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium t-butanolate In toluene at 30℃;	82%

montelukast tert-butylamine salt (851755-58-3) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: montelukast tert-butylamine salt With acetic acid In dichloromethane; water for 0.5h; Industry scale; Stage #2: With sodium hydroxide In methanol for 0.333333h; Industry scale;	75.4%
With sodium methylate In methanol at 25 - 35℃; for 1h; Product distribution / selectivity;
Stage #1: montelukast tert-butylamine salt With acetic acid In dichloromethane; water at 25 - 35℃; for 0.25h; Stage #2: With sodium hydroxide; pyrographite In methanol at 25 - 35℃; for 0.5h;

[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid homoveratrylamine salt (1187364-41-5) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid homoveratrylamine salt With acetic acid In dichloromethane; water at 0 - 5℃; Stage #2: With sodium hydroxide In methanol at 25 - 35℃; Product distribution / selectivity;	75%

C39H43ClN2O2S (1020313-99-8) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium hydroxide; water; ethylene glycol at 120 - 195℃; for 3 - 25h; Product distribution / selectivity;	60%

(1-{1-(R)-(E)-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid diisobutylamine salt (1399184-58-7) → Montelukast sodium (151767-02-1)

Conditions	Yield
With sodium tert-pentoxide In methyl cyclohexane; toluene at 20 - 45℃; for 1.5h;	56%
With sodium tert-pentoxide In toluene at 40 - 45℃; for 0.5h; Product distribution / selectivity; Inert atmosphere;	56%

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 (1008509-41-8) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With tartaric acid In water for 1h; Stage #2: With sodium hydroxide In methanol for 1h; Product distribution / selectivity;

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 (945934-73-6) → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 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 With tartaric acid In water for 1h; Stage #2: With sodium hydroxide In methanol for 1h; Product distribution / selectivity;

1-[[[(1R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl] cyclopropane acetic acid magnesium salt → Montelukast sodium (151767-02-1)

Conditions	Yield
Stage #1: 1-[[[(1R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl] cyclopropane acetic acid magnesium salt With acetic acid In water at 25 - 30℃; for 0.5h; Stage #2: With sodium hydroxide In ethanol; water at 25 - 30℃; for 0.5h;

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 sodium (151767-02-1)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; methanol; water at 24 - 27℃; for 20h; Product distribution / selectivity; Alkaline aqueous solution;
With sodium hydroxide In tetrahydrofuran; methanol at 20 - 25℃; for 50h;
With sodium hydroxide In tetrahydrofuran; ISOPROPYLAMIDE at 40℃; for 4h;

sodium hydroxide (1310-73-2) + montelukast tert-butylamine salt (851755-58-3) → Montelukast sodium (151767-02-1)

Conditions	Yield
In methanol at 5 - 10℃; for 0.5h; Product distribution / selectivity;

sodium hydroxide (1310-73-2) + n-butylamine salt of montelukast (1028683-07-9) → Montelukast sodium (151767-02-1)

Conditions	Yield
In methanol at 5 - 10℃; for 0.5h; Product distribution / selectivity;

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%

3,4,5-trifluorophenylboronic acid (143418-49-9) + Montelukast sodium (151767-02-1) → C41H38F3NO3S

Conditions	Yield
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; C28H26N2O8Pd2S2 In tetrahydrofuran at 100℃; for 5h; Suzuki-Miyaura Coupling; Inert atmosphere; Schlenk technique;	89%

3,4,5-trifluorophenylboronic acid (143418-49-9) + Montelukast sodium (151767-02-1) → C41H38F3NO3S

Conditions	Yield
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; {2-[((acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate) In tetrahydrofuran at 100℃; for 5h; Suzuki-Miyaura Coupling; Inert atmosphere;	89%

dimethyl sulfate (77-78-1) + Montelukast sodium (151767-02-1) → 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 (855473-51-7)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane Reflux;	54%

Montelukast sodium (151767-02-1) → [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]-phenyl]-3-[2-(-hydroxy-1-methylethyl) phenyl]propyl]-sulfinyl] methyl] cyclopropaneacetic acid

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid In dichloromethane at -22℃; for 2h; Yield given;
Stage #1: Montelukast sodium With dihydrogen peroxide In methanol; water for 3h; Stage #2: With acetic acid
With dihydrogen peroxide In methanol; water for 3h;

Upstream product

• 1310-73-2 sodium hydroxide 
• 158966-92-8 montelukast 
• 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 
• 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 
• 918972-53-9 montelukast isopropylamine salt 
• 851755-58-3 montelukast tert-butylamine salt 
• 880769-26-6 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 
• 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 
• 942303-96-0 montelukast N-methyl-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 
• 1028683-07-9 n-butylamine salt of montelukast 
• 1028683-09-1 isobutylamine salt of montelukast 
• 1028683-23-9 sec-butylamine salt of montelukast 
• 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 

Downstream Products

• 158966-92-8 montelukast 
• 1178966-47-6 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl) acetic acid hydrochloride 
• 780755-34-2 montelukast sodium; acetonitrile monosolvate 
• 934545-03-6 montelukast cetyl-pyridinium 
• 943438-55-9 montelukast lauro-cholinium 
• 1187586-61-3 [R, E]-[[1-[3-[2-(7-chloro-2-quinolinyl)-2-(S)-[(carboxymethyl)cyclopropyl]methyl]thio]ethyl]phenyl]-3-[[[[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid 
• 1187586-58-8 [R, E]-[[1-[3-[2-(7-chloro-2-quinolinyl)-2-(R)-[(carboxymethyl)cyclopropyl]methyl]thio]ethyl]phenyl]-3-[[[[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid 
• 774538-96-4 1-[[[(1R)-1-[3-[(lZ)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid 
• 918972-53-9 montelukast isopropylamine salt 
• 1100021-00-8 montelukast n-propylamine salt 
• 1334676-80-0 [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[(prop-1-en-2-yl)phenyl]propyl]thio]methyl]cyclopropane acetic acid methyl ester 
• 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 

Relevant articles and documents

Preparation method of montelukast sodium

The invention discloses a preparation method of montelukast sodium. The method comprises the following steps of: reacting a low-boiling-point organic amine salt of montelukast acid with alcohol serving as a solvent and an alcoholic solution of sodium hydroxide serving as alkali, performing concentrating under reduced pressure after the reaction is finished, adding water to dissolve to a specifiedconcentration, and conducting freeze-drying according to a corresponding freeze-drying procedure to obtain a montelukast sodium finished product meeting the requirements. The preparation method of montelukast sodium provided by the invention has the advantages of simple process, environmental protection, reduction of the use of a large amount of organic solvents, accordance with the characteristics of green chemistry and the like.

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,

Synthesis method of montelukast sodium

The invention belongs to the technical field of medicines, and particularly provides a montelukast sodium synthesis method, which comprises: (1) dissolving a compound represented by a formula (II) andan organic alkali in an organic solvent A under the protection of an inert gas, cooling, adding a tetrahydrofuran solution of a compound represented by a formula (III), and carrying out a stirring reaction to obtain a compound represented by a formula (IV); and (2) under the protection of inert gas, dissolving the compound represented by the formula (IV) in methanol, controlling the temperature,adding sodium hydroxide, adding a drying agent and activated carbon after the reaction is finished, stirring, filtering, concentrating under reduced pressure to obtain a compound crude product represented by a formula (I), and re-crystallizing the compound crude product represented by the formula (I) to obtain a compound refined product represented by the formula (I). According to the invention, the yield of the montelukast acid prepared according to the method is greater than 98%, the purity is higher than 99.7%, the yield of the prepared montelukast sodium is greater than 93.5%, and the purity is higher than 99.80%.

A synthesis process of montelukast sodium (by machine translation)

A synthesis process of montelukast sodium, relates to the field of drug synthesis, adopts a double hydroxy precursor of a sulfonyl derivative, and mercapto carboxylic acid compound, b cyclohexylamine in the reaction under the action of a catalyst, to obtain the ammonium salt, the quaternary ammonium salt is converted into the montelukast sodium. Compared with the direct synthesis of montelukast sodium, synthetic ammonium salt reaction not only conversion is higher, but also easy to separate, high purity, thus being beneficial to obtain high-purity of montelukast sodium. The synthesizing process of the synthetic route is simple, easy to operate, low requirements on equipment, can realize the large-scale production of montelukast sodium. (by machine translation)

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.

Method for preparing montelukast acid

The invention discloses a method for preparing montelukast acid. The method comprises a reaction b or a reaction a to a reaction b in the following synthetic route: the formula is shown in the description. The method disclosed by the invention can be used for preparing montelukast acid and salts thereof with low cost and high yield by means of simple operations by using low-cost and easily available raw materials, and is of significance and has practical value to prepare montelukast acid and salts thereof with low cost on a large scale.

METHOD FOR MANUFACTURING MONTELUKAST SODIUM

PROBLEM TO BE SOLVED: To provide a method for efficiently manufacturing high purity montelukast sodium without producing montelukast free acid. SOLUTION: There is provided a method of manufacturing high purity montelukast sodium by making a strong basic aqueous solution of sodium act on a montelukast amine salt represented by the following formula I, where R1 and R2 represent each independently hydrogen, an alkyl group or a cycloalkyl group, and R3 represents an alkyl group or a cycloalkyl group. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT

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%.

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.

Preparation method of montelukast sodium

The invention discloses a preparation method of montelukast sodium. The method comprises: A, converting a montelukast acid crude into a montelukast amino acid 2-amino-1-butanol salt; B, recrystallizing and refining the montelukast amino acid 2-amino-1-butanol salt; C, acidizing the montelukast amino acid 2-amino-1-butanol salt after refining, and freeing to obtain high-purity montelukast acid; and D, converting the montelukast acid into montelukast sodium. The preparation method of montelukast sodium has the advantages of simple process, high yield and good impurity removing effect, and the purity of the prepared montelukast sodium is more than 99.9%.