FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10; rule 13)



APPLICANTS
STERLING BIOTECH LIMITED
an Indian company having its registered office at
43, Atlanta Building, Nariman Point, Mumbai, Maharashtra 400 021
and Works at Jambusar State Highway,
Village Masar 391421, Taluka Padra, District Vadodara, Gujarat, India
INVENTORS
Sugata Chatterjee, Ajay Singh Rawat, Neeraj Kumar,
Mukesh Chavda and Rushikesh Kadu all Indian nationals of
STERLING BIOTECH LIMITED an Indian company
having its Works at Jambusar State Highway,
Village Masar 391421, Taluka Padra, District Vadodara, Gujarat, India
PREAMBLE TO THE DESCRIPTION
The following complete specification particularly describes the nature
of the invention and the manner in which it is to be performed.


FIELD OF INVENTION
The present invention relates to an improved, scalable and environment friendly
manufacturing procedure for the preparation of E-3-[2-(7-chloro-2-
quinolinyl)ethenyl]benzaldehyde, a key early intermediate used in.the preparation of
Montelukast sodium.
Montelukast sodium (Singulair) is described chemically as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thiomethyl]cyclopropane acetic acid sodium. It is a selective and orally active leukotriene receptor anatagonist that inhibits the cysteinyl leukotriene CysL Ti receptor and is useful in the treatment of asthma as well as other conditions mediated by leukotrienes like prevention of exercise induced bronchospasm. Montelukast is also used for the symptomatic treatment of seasonal or perennial allergic rhinitis and has also been evaluated for the management of urticaria.
BACKGROUND OF INVENTION
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Montelukast sodium a leukotriene antagonist useful in the treatment of asthma and related problems, described as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl] phenyl]-3-[2-(l-hydroxy-lmethylethyl)phenyl]propyl]thiomethyl]cyclopropane acetic acid sodium has the following structural formula I


The complete synthesis of Montelukast sodium is described in European publication 0,40,717, This patent does not mention the process for the preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde which is the first key intermediate in the synthesis of Montelukast sodium and represented by the following structural formula
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II
but provides the cross reference US 4,851,409 by Young et.al. In this patent (II) is reported to be synthesized by reacting 1.0 molar equivalent of isophthaldehyde with 1.08 molar equivalents of 7-chloroquinaldine in acetic anydride at 125°C for 48.0 hrs and the crude product isolated via filtration after precipitation with ether. The discussed method has the following drawbacks,
The reaction uses acetic anhydride which is a regulated commercial item as it is rampantly used for making banned narcotic drugs, hence making the process commercially unviable and unsafe.
Since II is an early intermediate the amount of acetic anhydride to be used is large. Use of acetic anhydride on large scale is very much inconvenient due to all the hazards associated with it (page 19 of Sax's 11th edition, Dangerous Properties of Industrial Materials, by Richard J. Lewis, Sr., Volume 2). The reaction time is long.
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Isolation step involves precipitation by the addition of ether to the reaction mixture
use of which is not safe and economical for large scale manufacturing, due its high
volatility and flammability.
Further the disclosed process does not mention the quality and yield of the obtained
intermediate.
Another patent application GB 2322624 A describes the process for the preparation of this key intermediate. Herein the reaction of 7-chloroquinalidine and isophthaldehyde is performed in the presence of acetic anhydride in a binary mixture of toluene and n-heptane in a preferred ratio of 25: 75 at 99-101°C for 13.0 hours. However, this described process suffers from the following major drawbacks
Firstly, this discussed process also uses acetic anhydride and thus carries the associated drawbacks mentioned above.
The reaction is carried out in a binary mixture of toluene and n-heptane making the process uneconomical when scaled up,
Also as per the discussed process, excess of the binary solvent mixture (toluene/ n-heptane) is added after completion of reaction as a filtration aid thus increasing the said effluent load.
The discussed process does not disclose the recyclability of the used binary solvent
system.
The discussed process emphasizes only the yield and does not mention about the
quality.
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The patent also exhibits examples in which reactions are performed in xylene and dry n-butyi acetate, which may not be economically viable to be employed for manufacturing purposes.
In another prior art WO 2006/021974 reaction of 7-Chloroquinalidine with isophthaldehdye in the presence of acetic anhydride in toluene at 100-105 C for 12-15 hours is described. This process has the following shortcomings
Firstly, the described process also uses acetic anhydride which accompanies the associated drawbacks mentioned earlier.
After completion of the reaction, excess n-hexane is added to the reaction mixture to facilitate precipitation and filtration creating a binary solvent mixture of toluene and hexane, an undesirable effluent load.
Also the described process does not teach us the fate of the used toluene and hexane mixture thus making the process uneconomical and eco-unfriendly for large scale manufacturing.
SUMMARY OF THE INVENTION
The aim of the present invention is to overcome the drawbacks as encountered in the prior art and provide an improved, scalable, efficient and an eco-friendly manufacturing procedure for the preparation of 3-[2-(7-chloro-2-quinolnyl)ethenyl]benzaldehyde, a key initial intermediate used in the preparation of Montelukast sodium.
It is the objective of the present invention to provide an improved, scalable and efficient manufacturing procedure for the preparation of 3-[2-(7-chloro-2-
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quinolinyI)ethenyl]benzaldehyde a key intermediate used in the preparation of Montelukast Sodium wherein the reaction is performed in a suitable single organic solvent.
It is another remarkably significant objective of the present invention to provide an improved, scalable and efficient manufacturing procedure for the preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde a key intermediate used in the preparation of Montelukast Sodium wherein the reaction is performed without acetic anhydride.
It is another objective of the present invention to provide an improved, scalable and efficient manufacturing procedure for the preparation of 3-[2-(7-chloro-2-quinoIinyl)ethenyl]benzaIdehyde a key intermediate used in the preparation of Montelukast Sodium wherein the reaction is performed in the presence of a suitable base, acid or a combination thereof.
The objectives as mentioned above will be apparent in the following detailed description.
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DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is illustrated in scheme I and is described below.

/\^\ O O
cAXXs+ "JSQ^H
III IV
Acetic anhydride or Acetic Acid or Pyridine: Acetic Acid n Heptane

V Bisadduct Ethyl acetate
I

II
Scheme I
Accordingly the present invention provides an improved, scalable and efficient manufacturing procedure for the preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaIdehyde, a key initial intermediate used in the preparation of Montelukast sodium, which comprises of;
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(1) Reacting 7-chloroquinaIdine (III) and isophthaldehyde (IV) in the presence of suitable base, acid or a combination thereof optionally in a suitable organic solvent or without solvent.
(2) Isolating the crude intermediate by direct filtration from the reaction mass.
(3) Purifying the crude intermediate.
(4) Recovering the organic solvent from mother liquor by atmospheric or vacuum distillation, if so desired, and using the recovered solvent for the said reaction.
As per the present invention the suitable single organic solvent for the reaction may be a linear or branched C 5 to C 10 hydrocarbon one, such as, for example, n-pentane, n-hexane, hexanes, n-heptane, heptanes, n-octane etc, aromatic hydrocarbons such as for example, toluene, xylene etc. The most preferred solvent is n-heptane.
The present invention further provides a process wherein the reaction is carried out at any temperature between ambient and reflux temperature of the chosen organic solvent.
The present invention further provides a process wherein 0.9 to 3.0 molar equivalent of isophthaldehyde with respect to 7-chloroquinaldine is used in the reaction. The preferred amount of isophthaldehyde to be used is 0.98 to 1.50 molar equivalent, most preferably 1.30 to 1.50 molar equivalent.
The present invention further provides a process wherein the suitable base is chosen from pyridine, piperidine, triethylamine, diisopropylethylamine etc., most preferably pyridine.
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mol, l.Oeq) in n-heptane (30ml, 6vol) was heated at reflux for 8-9 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated crude solid was filtered. The wet crude product was charged to 150.0 ml. ethyl acetate and heated to reflux with stirring for 2 hrs. The solution was filtered hot and was then concentrated under vacuum to -10.0 ml. The resultant slurry was cooled below 20 °C and stirred at the same temperature for 2 hrs. The solid was then filtered, washed with chilled ethyl acetate and dried at 55-60 °C under vacuum for 5.0 hours. Yield 4.40 gm (55.04%), Purity (HPLC) 99.42 %.
Example 2
A solution of 7-chloroquinaldine (5.0g, 0.028mol, l.Oeq), isophthaldehyde (5.63g, 0.042mol, 1.5eq), pyridine (2.26 ml, 0.028 mol, l.Oeq) and acetic acid (1.6 ml, 0.028 mof, I.Ceq) in tofuene (30ml, 6voi) was heated at reflux for 8-9 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated crude solid was filtered. The wet crude product was charged to 150 ml. ethyl acetate and heated to reflux with stirring for 2 hrs. The solution was filtered hot and then concentrated under vacuum to -10.0 ml. The resultant slurry was cooled below 20 °C and stirred at same temperature for 2 hrs. The solid was then filtered, washed with chilled ethyl acetate and dried at 55-60 °C under vacuum for 5.0 hours. Yield 3.96 gm (48.0%), Purity (HPLC) 99.63 %.
Example 3
A solution of 7-chloroquinaldine (25g, 0.141mol, l.Oeq), isophthaldehyde (28.38g, 0.212mol, 1.5eq), acetic acid (8.4 ml, O.Hlmol, l.Oeq) in n-heptane (150ml, 6vol) was heated at reflux for 6-7 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated crude solid was filtered. The wet crude product was charged to 750.0 ml. ethyl acetate and heated to reflux with stirring for 2 hrs. The solution was filtered in hot and was then concentrated under vacuum to -50.0 ml. The resultant slurry was cooled below 20 °C and stirred at same temperature for 2
10

hrs. The solid was then filtered, washed with chilled ethyl acetate and dried at 55-60
°C under vacuum for 5.0 hours.
Yield 26.3 gm (63.75%), Purity (HPLC) 99.84 %.
Example 4
A solution of 7-chloroquinaldine (25g, O.HlmoI, l.Oeq), isophthaldehyde (28.38g, 0.212mol, 1.5eq), acetic acid (8.4 ml, O.HlmoI, l.Oeq) in toluene (150ml, 6 vol) were heated at reflux for 6-7 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated crude solid was filtered. The wet crude product was charged to 750.0 ml. ethyl acetate and heated to reflux with stirring for 2 hrs. The solution was filtered in hot and was then concentrated under vacuum to -50.0 ml. The resultant slurry was cooled below 20 °C and stirred at same temperature for 2 hrs. The solid was then filtered, washed with chilled ethyl acetate and dried at 55-60 °C under vacuum for 5.0 hours. Yield 18.56 gm (45.0%), Purity (HPLC) 99.89 %.
Example 5
A solution of 7-chloroquinaldine (100 g, 0.565mol, l.Oeq), isophthaldehyde (113.54g, 0.847mol, 1.5eq), in acetic acid ((200ml, 2vol) were heated at 100°C for 1-2 hr. The reaction mixture was allowed to cool to room temperature. The precipitated crude solid was filtered and washed with 200 ml methanol. The wet crude product was charged to 3000 ml ethyl acetate and heated to reflux with stirring for 2 hrs. The solution was filtered in hot and was then concentrated under vacuum to -200.0 ml. The resultant slurry was cooled below 20 °C and stirred at same temperature for 2 hrs. The solid was then filtered, washed with chilled ethyl acetate and dried at 55-60 °C under vacuum for 5.0 hours. Yield 108.2 gm (65.45%), Purity (HPLC) 99.94 %.
Table 2 summarizes some of the examples of the present invention while Table 1 shows the results obtained by using acetic anhydride as a reference for comparison.
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Table-1 Preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde (II) Using acetic anhydride

Expt.
No Chemicals Solvent Time (hrs) II
Yield (Molar %) HPLC Purity
% Impurity
V (Molar
%)
1. III(1.0eq.),IV(1.30eq), Acetic Anhydride (1.5eq.) n-Heptane 6.0 54.41 98.95 7.03
2. III(1.0eq.),IV(1.50eq), Acetic Anhydride (1.5eq.) n-Heptane 6.0 54.41 99.58 7.81
3. III(1.0eq.),IV(1.50eq), Acetic Anhydride (1.5eq.) Heptane -Toluene 6-7 45.20 99.66 3.90
4. Ill (l.Oeq.), IV (1.50eq), Acetic Anhydride (1.5eq.) n-Heptane (recovered) 7.0 65.34 99.60 8.12
5. Ill (l.Oeq.), IV (1.50eq), Acetic Anhydride (1.5eq.) Acetonitrile 6.0 8.43 94.52 1.95
6. Ill (l.Oeq.), IV (1.50eq), Acetic Anhydride (1.5eq.) 1,4-Dioxane 6.0 39.18 99.35 1.79
7. Ill (l.Oeq.), IV (1.50eq), Acetic Anhydride (1.5eq.) N,N-Dimethylformamide 6-7 30.13 95.85 2.26
8. Ill (l.Oeq.), IV (1.50eq), Acetic Anhydride (1.5eq.) Dimethyl sulfoxide 6-7 36.16 97.68 1.87

Table-2 Preparation of 3-[2-(7-chloro-2-quinolinyl) ethenyl] benzaldehyde (II) without using acetic anhydride

Expt
No. Chemicals Base/Acida Solvent Reaction Time (hrs) a
Yield (Molar %) HPLCb Purity
% Impurity V (Molar %)
1. III (l.Oeq), IV (1.30eq) Pyridine - Acetic
acid* (l.Oeq) n-Heptane 7.0 48.42 97.99 3.90
2. III (l.Oeq), IV (1.50eq) Pyridine-Acetic
acid (1-Oeq) n-Heptane 7.0 53.04 99.42 7.81
3. III (l.Oeq), IV(1.50eq) Pyridine - Acetic
acid (l.Oeq) Toluene 7.0 48.39 99.63 5.46
4. III(1.0eq),IV(1.50eq) Acetic acid
(1-Oeq.) n-Heptane 6.0 63.64 99.84 8.62
5. III(1.0eq),IV(1.50eq) Acetic acid
(l.Oeq.) Toluene 12.0 41.14 99.89 5.48
6. III(1.0eq),IV(1.50eq) Acetic acid
(l.Oeq.) n-Heptane-Toluene 6.0 30.13 98.65 3.51
7. III (l.Oeq), IV (1.50eq) Acetic acid Acetic Acid 1.0-2.0 65.45 99.94 7.75
a : Commercially available glacial acetic acid ~98.0% pure by GC was used for the reaction purpose.
b : HPLC Conditions: Column: Waters Spherisorb 250 X 0.4 cm, 5um, Buffer: PBS: Methanol (30:70), pH = -3.0, flow rate: 1,0 ml/min, Detection at 260 nm

We Claim:
1. A process for the preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde (II) represented by the following structure

II
which comprises of;
(a) reacting 7-chloroquinaldine (III) with isopthaldehyde (IV) in the presence of a base, acid or a combination thereof in a single organic solvent

V Bisadduct
(b) isolating the crude compounds by filtration from the reaction mixture and
(c) purifying the wet crude to remove the bis adduct of formula V by crystallization from an organic solvent.
2. The process as claimed in any of the preceding claims, wherein 0.90 to 3.0 molar equivalent of isopthaldehyde is used.
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3. The process as claimed in any of the preceding claims, wherein the reaction is performed without using acetic anhydride.
4. The process as claimed in any of the preceding claims, wherein the reaction is carried out in the presence of a suitable base.
5. The process as claimed in any of the preceding claims, wherein the reaction is carried out in the presence of an acid.
6. The process as claimed in any of the preceding claims, wherein the reaction is carried out in the presence of a combination of a base and acid.
7. The process as claimed in any of the preceding claims, wherein the organic solvent for the reaction is chosen from C5 to CIO linear or branched chained aliphatic or aromatic hydrocarbon.
8. The process as claimed in any of the preceding claims, wherein the reaction is carried out at ambient to reflux temperature of the organic solvent.
9. The process as claimed in claim 5, wherein pyridine is the base.
10. The process as claimed in claim 6, wherein acetic acid is the acid.
11. The process as claimed in claim 7, wherein the combination of a base and acid is selected from triethylammonium acetate, triethylammonium chloride, diisopropylammonium acetate, diisopropylammonium chloride, piperidinium acetate, piperidinium chloride, pyridinium chloride, pyridinium acetate, most preferably pyridinium acetate.
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12. The process as claimed in any of the preceding claims, wherein acetic acid is the acid as well as the solvent for the reaction.
13. The process as claimed in any of the preceding claims, wherein n-heptane is the organic solvent for the reaction.
14. The process as claimed in any of the preceding claims, wherein heptanes are the organic solvent for the reaction.
15.A process for the preparation of 3-[2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde (II) substantially as herein described and exemplified.
Dated this 23rd day of July 2008

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