Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

“IMPROVED PROCESS FOR THE PREPARATION OF MONTELUKAST SODIUM”

We, ZENFOLD SUSTAINABLE TECHNOLOGIES PRIVATE LIMITED an Indian company of 53 C, Praga Square, Bommasandra Industrial Area, Phase 1, Hosur Road, Bengaluru, Karnataka- 560099, India;

The following specification particularly describes the invention & the manner in which it is to be performed.
Field of the invention
The disclosure relates to an improved process for the preparation of montelukast sodium.

Background of the invention
Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. It is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The structural formula is:

Montelukast sodium (Formula I)

It is sold under the brand name SINGULAIR® and is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.

Various processes for the preparation of montelukast were disclosed in the art for example EP0480717B1, US 5,614,632, US 7,547,787, US 8,178,680, US 8,207,343, US 8,450,491, US 8,426,599, US20050107612, WO2009138993, WO2014001860.

The PCT patent publication no. WO2014001860 discloses is a process for the preparation of montelukast sodium. The process comprises a) reacting 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol with methane sulfonyl chloride and coupling the resultant mesylate compound with 1-(mercaptomethyl)cyclopropane acetic acid in presence of a base and free alkali source followed by saltification with an amine in a single step reaction and b) converting the montelukast amine salt to montelukast sodium salt. However, this process involves use of mixture of solvents. Further, this process involves unit operations such as filtration, for example the process involves filtration of reaction mixture of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol with methane sulfonyl chloride to obtain filtrate containing mesylate compound which is then used for coupling in next reaction.

Several processes have been described in the art for the preparation of montelukast sodium however; still there is a need for a process for preparation of montelukast that can be performed in a single solvent and having lesser unit operations.

Summary of the invention
The specification discloses an improved process for the preparation of montelukast sodium comprising:
(a) reacting compound of formula II
(Formula II)
with compound of formula III
NaOR1
(Formula III)
wherein R1 is hydrogen, methyl, ethyl, isopropyl or tert-butyl;
to obtain a solution of compound of formula IV

(Formula IV)
(b) reacting compound of formula V

(Formula V)
with compound of formula VI
RSO2Cl
(Formula VI)
wherein R is methyl, p-toluene or phenyl;
to obtain a solution of compound of formula VII

(Formula VII)
(c) adding the solution of step (a) to the solution of step (b) to form crude montelukast free acid,
(d) extracting crude montelukast free acid in water immiscible solvent,
(e) adding organic base to obtain motelukast organic base salt,
(f) recrystallization of motelukast organic base salt with an organic solvent,
(g) neutralizing the montelukast organic base salt with an acid to obtain motelukast free acid and
(h) optionally, converting motelukast free acid to motelukast sodium.
wherein reaction of step (a), step (b) and step (c) are carried out in a single solvent, and
wherein step (b) does not involve filtration of solution of compound of formula VII.

Brief description of the drawing
Figure 1. Synthetic scheme for the preparation of montelukast.

Detailed description
The disclosure is essentially directed towards an improved process for the preparation of montelukast sodium comprising:
(a) reacting compound of formula II; 1-(mercaptomethyl)cyclopropane acetic acid
(Formula II)
with compound of formula III
NaOR1
(Formula III)
wherein R1 is hydrogen, methyl, ethyl, isopropyl or tert-butyl;
to obtain a solution of compound of formula IV; 1- (mercaptomethyl)cyclopropane acetic acid disodium

(Formula IV)
(b) reacting compound of formula V; 2-(2-(3(S)-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol

(Formula V)
with compound of formula VI
RSO2Cl
(Formula VI)
wherein R is methyl, p-toluene or phenyl;
to obtain a solution of compound of formula VII; sulfonyl derivative of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- hydroxypropyl)phenyl)-2-propanol

(Formula VII)
(c) adding the solution of step (a) to the solution of step (b) to form crude montelukast free acid,
(d) extracting crude montelukast free acid in water immiscible solvent,
(e) adding organic base to obtain motelukast organic base salt,
(f) recrystallization of motelukast organic base salt with an organic solvent,
(g) neutralizing the montelukast organic base salt with an acid to obtain motelukast free acid and
(h) optionally, converting motelukast free acid to motelukast sodium.
wherein reaction of step (a), step (b) and step (c) are carried out in a single solvent, and
wherein step (b) does not involve filtration of solution of compound of formula VII.

In the main embodiment, the reaction of step (a), step (b) and step (c) are performed in a single solvent. ‘A single solvent’ means the same solvent for example, if the step (a) is performed in tetrahydrofuran then the step (b) and step (c) are also performed in tetrahydrofuran.

Step (a) is preparation of solution of compound of formula IV. In step (a), 1-(mercaptomethyl)cyclopropane acetic acid (compound of formula II) is reacted with compound of formula III in a solvent to obtain a solution of 1-(mercaptomethyl)cyclopropane acetic acid disodium (compound of formula IV).
The step (a) is performed at temperature from -20 °C to 20 °C, preferably -10 °C to 0 °C.

The solvent used in step (a) is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, nitrobenzene, tert-butanol or acetonitrile.

Step (b) is preparation of solution of compound of formula VII. In step (b), 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol (compound of formula V) is reacted with sulfonyl chloride compound (compound of formula VI) in presence of an organic base to obtain solution of compound of formula VII. The step (b) is performed at temperature from -60 °C to 0 °C, preferably -40 °C to -20 °C. The organic base is selected from triethylamine, diisopropylethylamine, 3-picoline, pyridine or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), preferably diisopropylethylamine.

In step (c) solution of compound of formula IV is added to the solution of compound of formula VII in presence of an inorganic base. The step (c) is performed at temperature from -50 °C to 50 °C. The inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium hydroxide or potassium hydroxide.

In step (d), the reaction mixture of step (c) is quenched with aqueous sodium chloride solution and water immiscible solvent is added to the reaction mixture. The pH of reaction mixture is adjusted to 5.0 using 50% aqueous acetic acid. Organic layer containing crude montelukast free acid is separated and used in the next step. The water immiscible solvent used for extraction in step (d) is selected from toluene, dichloromethane, dichloroethane or ethyl acetate, preferably toluene.

In step (e), organic base is added to the solution of step (d) to obtain motelukast organic base salt. The organic base is selected from tributylamine, 1-methyl-3-phenylpropyl amine or dicyclohexyl amine, preferably tributylamine. In one specific embodiment, motelukast tributylamine salt is prepared.

Step (f) is the purification of motelukast organic base salt. Motelukast organic base salt is recrystallized with an organic solvent selected from ethylacetate, toluene, chlorobenzene or nitrobenzene, preferably toluene. In one specific embodiment, motelukast tributylamine salt is recrystallized from toluene. The recrystallization may be performed repeatedly till the desired purity is achieved.

Step (g) is neutralization of the montelukast organic base salt with an acid to obtain motelukast free acid. The acid is selected from acetic acid or tartaric acid, preferably acetic acid. The neutralization may be performed in a suitable solvent such as toluene, chloroform, dichloromethane or dichloroethane.

Step (h) is preparation of motelukast sodium from motelukast free acid. In step (h), motelukast free acid is treated with a sodium base in a solvent to obtain motelukast sodium. The sodium base is selected from sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide or sodium tert-butoxide and the solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or tetrahydrofuran.

The following example illustrate specific embodiment; however, the full scope of the disclosure is not limited to the example described below. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. For example, dimethylformamide used in example 1 can be replaced by the other solvents described in the description of the invention. Such changes and modifications may be made without departing from the scope of the invention.

EXAMPLE
Example 1
Preparation of solution of compound of formula IV:
Compound of formula II (40 g) in was taken in a vessel containing dimethylformamide (250 mL). Sodium methoxide (30 g, 0.56 mol) was added at 0 °C and stirred for 1 h at 0 °C.

Preparation of solution of compound of formula VII:
Methane sulfonyl chloride (30 g, 0.26 mol) was added slowly (1 mL/min) to a mixture of compound of formula V (100 g, 0.22 mol) and diisopropylethylamine (50.6 g, 0.39 mol) in dimethylformamide (500 ml) at -35 °C. As conversion gets completed, sodium isopropoxide (29g) was added lot wise to the reaction mixture at -35 °C.

Preparation of montelukast:
Solution of compound of formula IV was added slowly to solution of compound of formula VII at -35 °C to -25 °C and stirred for 5 h at 0 °C. The reaction mixture was quenched with 20% aqueous sodium chloride solution (200 mL) at 0 °C. Toluene (400 mL) was charged to the reaction mixture. The pH of reaction mixture was adjusted to 5.0 using 50% aqueous acetic acid. Layers were separated and aqueous layer was washed with toluene (2 x 150 mL). The combined toluene phase was washed successively with 3% aqueous sodium bicarbonate solution (2 x 100 mL and 30% aqueous sodium chloride solution (1 x 100 ml). Tributylamine (18 g, 0.24 mol) was added to the toluene phase and allowed to stir at 25 °C for 15 h. The precipitated montelukast tributylamine salt was filtered and washed with 100 mL of toluene. Wet material was dried under vacuum at 55 °C until it gets constant weight. Yield: 130 g; Purity 94%; Methyl styrene: 0.4%; Michael adducts: 1.0%.

The above salt (130 g) was taken in toluene (650 mL) and heated the mixture to 90 °C for 2 h followed by at 50 °C for 12 h. The mixture was cooled to 20 °C to 25 °C, filtered and the filtrate was washed with 130 ml of toluene at 25 °C. Wet material was dried under vacuum at 55 °C until it gets constant weight. Yield: 120 g; Purity: 98.5%; Methyl styrene: 0.22%; Michael adducts: 1.0%.

The salt obtained above was portioned between water (360 mL) and ethyl acetate (360 mL). The pH of aqueous layer was adjusted to 5.0 with 50% aqueous acetic acid under stirring at 20 °C to 25 °C. Layers were separated, and organic layer was washed successively with 3% (w/w) aqueous sodium bicarbonate solution (3 x 120 mL), and 25% aqueous sodium chloride solution (2 x 120 mL). The solvent was distilled out completely, and a 1;1 mixture of acetonitrile (30 mL) and methanol (30 mL) was added to the residue and stirred at 25 °C for 3 h. The slurry was filtered and washed with 12 mL of 1:1 mixture of acetonitrile and methanol at 20 °C to °C. Wet material was dried under vacuum at 55 °C until it gets constant weight. Yield: 102 g, Purity: 99.5%; Methyl styrene: 0.20%; Michael adducts: 0.10%.

Preparation of montelukast sodium:
A solution of sodium hydroxide (6.0 g) in methanol (500 mL) was added to a solution of montelukast free acid (100 g) in methanol (500 mL) at 20 °C to 25 °C. The reaction mixture was stirred for 2 h. Activated carbon (10 g) was charged to the reaction mixture and stirred for 1 hour. The reaction mass was filtered through a celite bed and washed with methanol (200 mL). Volatiles were distilled out under vacuum at 50 °C. The material was further dried in vacuum tray drier at 50 °C for 10 hours to get montelukast sodium (100 g), Purity: 99.5%; enantiomeric purity by HPLC: 99.99%; S-enantiomer: 0.01%.
, Claims:We Claim:

1. An improved process for the preparation of montelukast sodium comprising:
(a) reacting compound of formula II
(Formula II)
with compound of formula III
NaOR1
(Formula III)
wherein R1 is hydrogen, methyl, ethyl, isopropyl or tert-butyl;
to obtain a solution of compound of formula IV

(Formula IV)
(b) reacting compound of formula V

(Formula V)
with compound of formula VI
RSO2Cl
(Formula VI)
wherein R is methyl, p-toluene or phenyl;
to obtain a solution of compound of formula VII

(Formula VII)
(c) adding the solution of step (a) to the solution of step (b) to form crude montelukast free acid,
(d) extracting crude montelukast free acid in water immiscible solvent,
(e) adding organic base to obtain motelukast organic base salt,
(f) recrystallization of motelukast organic base salt with an organic solvent,
(g) neutralizing the montelukast organic base salt with an acid to obtain motelukast free acid and
(h) optionally, converting motelukast free acid to motelukast sodium.
wherein reaction of step (a), step (b) and step (c) are carried out in a single solvent, and
wherein step (b) does not involve filtration of solution of compound of formula VII.

2. The process according to claim 1, wherein the step (a), step (b) and step (c) are performed in the single solvent selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, nitrobenzene, tert-butanol or acetonitrile.

3. The process according to claim 1, wherein the step (a) is performed at temperature from -20 °C to 20 °C and step (b) is performed at temperature from -60 °C to 0 °C.

4. The process according to claim 1, wherein the step (b) is performed in presence of an organic base and the step (c) is performed in presence of an inorganic base.

5. The process according to claim 4, wherein the organic base is selected from triethylamine, diisopropylethylamine, 3-picoline, pyridine or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and wherein the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide cesium hydroxide or potassium hydroxide.

6. The process according to claim 1, wherein the step (c) is performed at temperature from -50 °C to 50 °C.

7. The process according to claim 1, wherein the organic base in step (e) is tributylamine.

8. The process according to claim 1, wherein the organic solvent in step (f) is toluene.

9. The process according to claim 1, wherein the step (h) is performed in presence of a sodium base selected from sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide or sodium tert-butoxide.

10. The process according to claim 1, wherein the step (h) is performed in the solvent selected from methanol, ethanol, isopropyl alcohol, tert-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or tetrahydrofuran.