Claims:We claim:

1. A process for preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A), comprising reacting 7-chloro-2-methyl-quinoline of formula (I) with 3-acetylbenzaldehyde of formula (II),
.

2. The process as claimed in claim 1, wherein the reaction is carried out in a solvent selected from the group of xylene, toluene, heptanes, hexane and cyclohexane and/or mixtures thereof.

3. The process as claimed in claim 1, wherein the reaction is carried out in toluene.

4. The process as claimed in claim 1, wherein the reaction is carried out at a temperature in a range of about 80°C - 120°C.

5. The process as claimed in claim 4, wherein the reaction is carried out at a temperature in a range of about 100°C - 110°C.

6. The process as claimed in claim 1, wherein the reaction is carried out in presence of an activator selected from Acetic acid and Acetic anhydride.

7. The process as claimed in claim 1, wherein the 3-acetylbenzaldehyde of formula (II) is prepared by a process comprising the steps of:
I) Reacting acetophenone with paraformaldehyde and aluminium chloride to form 1-[3-(chloromethyl)phenyl]ethanone;

II) X) i) reacting -[3-(chloromethyl)phenyl]ethanone with hexamethylenetetramine to form 1-[3-(hexamethylenetetraaminomethyl)phenyl]ethanone chloride of formula (IIIa); and
II) X) ii) treating hexamine salt of formula (IIIa) with acetic acid to form 3-acetylbenzaldehyde of formula (II).

Or
Y) i) Reacting 1-[3-(chloromethyl)phenyl]ethanone with a base to from 1-[3-(hydroxymethyl)phenyl]ethanone of formula (IIIb); and
Y) ii) oxidizing compound of formula (IIIb) to 3-acetylbenzaldehyde of formula (II).

8. The process as claimed in claim 7, wherein the step I) is carried out in a solvent selected from chloroform and methylene dichloride.

9. The process as claimed in claim 7, wherein the step I) is carried out in chloroform.

10. The process as claimed in claim 7, wherein the step I) is carried out at a temperature in a range of about at 0°C -40°C.

11. The process as claimed in claim 7, wherein the step I) is carried out at a temperature in a range of about 25°C -35°C.

12. The process as claimed in claim 7, wherein the step II) X) i) is carried out in a chlorinated solvent selected from the group of chloroform, MDC and chlorobenzene.

13. The process as claimed in claim 7, wherein the step II) X) i) is carried out in chloroform.

14. The process as claimed in claim 7, wherein the step II) X) i) is carried out at a reflux temperature.

15. The process as claimed in claim 7, wherein acetic acid used in the step II) X) ii) is 10% - 50% acetic acid.

16. The process as claimed in claim 7, wherein acetic acid in the step II) X) ii) is 25% acetic acid.

17. The process as claimed in claim 7, wherein the step II) X) ii) is carried out at a temperature of about 60°C -100°C.

18. The process as claimed in claim 7, wherein the step II) X) ii) is carried out at a temperature of about 80°C - 90°C.

19. The process as claimed in claim 7, wherein the base in the step II) Y) i) is selected from the group of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

20. The process as claimed in claim 19, wherein the base is sodium carbonate.

21. The process as claimed in claim 7, wherein the step II) Y) i) is carried out at a temperature of 100°C.

22. The process as claimed in claim 7, wherein the compound (IIIb) formed in the step II) Y) i) is isolated by a solvent selected from MDC and chloroform.

23. The process as claimed in claim 7, wherein the step II) Y) ii) is carried out by an oxidizing agent selected from manganese oxidizing agent or chromium based oxidizing agent.

24. The process as claimed in claim 23, wherein the manganese or chromium based oxidizing agents are selected from the group of potassium permanganate (KMnO4), potassium dichromate (K2Cr2O7), Johns’s reagent, pyridinium chlorochromate (PCC) and Manganese dioxide (MnO2).

25. The process as claimed in claim 7, wherein the step II) Y) ii) is carried out using potassium permanganate.

26. The process as claimed in claim 7, wherein the step II) Y) ii) is carried out using peroxy reagents.

27. The process as claimed in claim 26, wherein the peroxy reagents are selected from the group of hydrogen peroxide (H2O2), Sodium hypochlorite (NaOCl), Sodium hypobromide (NaOBr).

28. The process as claimed in claim 7, wherein the step II) Y) ii) is carried out in presence of catalyst 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl.

29. The process as claimed in claim 26, wherein the step II) Y) ii) is carried out in presence of a catalyst selected from sodium tungstate and ferric dodacane sulafonate.

30. A process for preparation of 3-acetylbenzaldehyde of formula (II) comprising the steps of:
I) reacting acetophenone with paraformaldehyde and aluminium chloride to form 1-[3-(chloromethyl)phenyl]ethanone;

II) X) i) reacting -[3-(chloromethyl)phenyl]ethanone with hexamethylenetetramine to form 1-[3-(hexamethylenetetraaminomethyl)phenyl]ethanone chloride of formula (IIIa); and
II) X) ii) treating hexamine salt of formula (IIIa) with acetic acid to form 3-acetylbenzaldehyde of formula (II).

Or
Y) i) reacting 1-[3-(chloromethyl)phenyl]ethanone with Sodium carbonate to from 1-[3-(hydroxymethyl)phenyl]ethanone of formula (IIIb); and
Y) ii) oxidizing compound of formula (IIIb) to 3-acetylbenzaldehyde of formula (II).

Dated this 10th day of May, 2016
FOR AARTI INDUSTRIES LIMITED
By their Agent

(Anand Gopalkrishna Mahurkar) (IN/PA 1862)
KRISHNA & SAURASTRI ASSOCIATES

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

“PROCESS FOR PREPARATION OF 1-[3-[(E)-2-(7-CHLORO-2-QUINOLYL) VINYL] PHENYL] ETHANONE”

AARTI INDUSTRIES LIMITED
AN INDIAN COMPANY
71, UDYOG KSHETRA, 2nd FLOOR,
MULUND GOREGAON LINK ROAD,
MULUND (W) MUMBAI- 400080,
MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the Invention

The present invention relates to Montelukast intermediates and more particularly a novel process for preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone.

Background and prior art

1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A), is well-known in the art as an important intermediate in the manufacturing of Montelukast and many other pharmaceutically active ingredients. The structure of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A) is illustrated below-

Various processes are known in art for the preparation of intermediate of formula (A).

For example, prior art patent documents US 5,270,324, US 5,565,473 and US 5,104,882 describe synthesis of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone involving reaction of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde with methyl magnesium bromide to give an ethanol derivative. The ethanol derivative was oxidized by portionwise addition of activated manganese dioxide. However, the purification of the intermediate generally requires flash chromatography.

Also, International Patent Publications WO 2006/021974 and WO 2008/058118 describe the process for preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A) by condensation of 7-chloroquinaldine with isophthaldehyde wherein the reaction mixture on reflux forms 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde. Isolated 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde was reacted with methyl magnesium bromide under Grignard conditions to form [3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl]ethanol, which was oxidized to 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone by Swern Oxidation.

However, condensation of 7-chloroquinaldine with isophthalaldehyde has number of significant disadvantages which limit the utility of the synthesis. These disadvantages mainly include formation of by-products, particularly dimer impurity which results in low yield. Also the condensation method needs many purification steps to get pure product and moreover results in overall yield of only 50-60%.

Moreover, Grignard Reaction which is needed for conversion of 3-(2-(7-chloro-2-quinolinyl)ethenyl) benzaldehyde to [3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl]ethanol, has mainly one or more of the following drawbacks. Grignard reagents readily react with oxygen and also with protic solvents such as water, alcohols and thiols. The atmospheric humidity can alter the yield of making Grignard reagent from Magnesium and alkyl halide. Thus, the reaction is water-sensitive and air-sensitive and needs extra care to prevent destroying of reagent by protolysis and oxidation. In addition, Grignard reactions are sluggish and may need some of the mechanical or chemical activating methods or commercially available Grignard Reagents to avoid the problem of initiation. This need results in increase in overall cost and makes the process economically inefficient. Further, said reaction is exothermic and hence there is always a need for special care and precaution while scaling-up in higher scale.

Thus there is a need of simple, efficient and industrially feasible method for the preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone that overcomes all the drawbacks of the prior art.

Objects of the invention

An object of present invention is to provide a novel process for synthesis of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone.

Another object of the present invention is to provide a process for synthesis of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone that avoids extensive purifications and work ups.

Yet another object of the present invention is to provide a process for preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone that avoids Grignard Reaction.

Still another object of the present invention is to provide a process for preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone which avoids formation of dimer-impurity and other by-products and provides 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl] ethanone in higher yield and purity.

Further object of the present invention is to provide processes for the preparation of 3-acetylbenzaldehyde and its use in the preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone.

Summary of the invention

An aspect of the present invention is to provide a process for preparing 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A). The process comprises condensation of 7-chloro-2-methyl-quinoline of formula (I) with 3-acetylbenzaldehyde of formula (II). The schematic representation of the process is represented as follows-

SCHEME 1
Another aspect of the invention is to provide a process for the preparing 3-acetylbenzaldehyde of formula (II). The process comprises reaction of Acetphenone with paraformaldehyde and aluminium chloride to form 1-[3-(chloromethyl)phenyl]ethanone, that is treated with hexamethylenetetramine in a chlorinated solvent to form 1-[3-(hexamethylenetetraaminomethyl)phenyl]ethanone chloride of formula (IIIa).

SCHEME 2
Alternatively, 1-[3-(chloromethyl)phenyl]ethanone is treated with base to form 1-[3-(hydroxymethyl)phenyl]ethanone of formula (IIIb). Compound of formula (IIIa) or (IIIb) is converted to 3-acetylbenzaldehyde of formula (II). The process is summarized as shown in scheme 2 above.

Detailed description of the invention

While this document contains many specifics, these should not be construed as limitations on the scope of an invention that is claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this document in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination.

Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results.
As used in the specification the singular forms "a" "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of solvents, reference to "an agent" includes mixtures of two or more such agents, and the like.

According to a preferred embodiment of the present invention, a process to prepare 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A) is described hereinafter. The said process comprises an initial step of condensation of 7-chloro-2-methyl-quinoline of formula (I) with 3-acetylbenzaldehyde of formula (II). The process of the present invention in this one preferred embodiment is as shown in scheme below-

The aforementioned reaction is preferaly carried out in presence of a solvent selected from the group of toluene, xylene, heptane, hexane, cyclohexane and/or mixture thereof, and most preferably toluene. The aforementioned reaction is preferably carried out at a temperature in a range of about 80°C – 120°C, and most preferably at the temperature in a range of about 100°C -110°C. The aforementioned reaction is carried out in presence of activator selected from acetic anhydride and acetic acid.

In this one embodiment, 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone of formula (A) is isolated and purified using a solvent selected from toluene, xylene, heptane, hexane, cyclohexane and/or mixture thereof, and most preferably using heptane and cyclohexane.

In another embodiment, the present invention provides a process for the preparation of 3-acetylbenzaldehyde of formula (II) wherein Acetphenone is reacted with paraformaldehyde and aluminium chloride to form 1-[3-(chloromethyl)phenyl]ethanone.

In this another embodiment, the reaction is preferably carried out in a solvent selected from chloroform and methylene dichloride, and most preferably in chloroform. In this one another embodiment, the reaction is carried out at a temperature in a range of about 0°C -40°C, and most preferably at the temperature of about 25°C - 35°C.

In this another embodiment, 1-[3-(chloromethyl)phenyl]ethanone is treated with hexamethylenetetramine in a chlorinated solvent to form 1-[3-(hexamethylenetetraaminomethyl)phenyl]ethanone chloride of formula (IIIa). It is understood here that the chlorinated solvent is selected from MDC, chloroform and chlorobenzene, and most preferably chloroform. In this one embodiment, the aforementioned reaction is carried out at a reflux temperature.

Hexamine salt of formula (IIIa) is treated with acetic acid to form 3-acetylbenzaldehyde of formula (II) wherein Acetic acid used in the reaction is 10%-50% acetic acid, and most preferably 25% acetic acid. The reaction in this one embodiment is carried out at a temperature of about 60°C -100°C, and most preferably at the temperature of about 80°C -90°C.

Alternatively, 1-[3-(chloromethyl)phenyl]ethanone is treated with a base to from 1-[3-(hydroxymethyl)phenyl]ethanone of formula (IIIb).

In this one alternative embodiment, the base is selected from Sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and most preferably the base selected is sodium carbonate. The aforementioned reaction is carried out at a temperature of 100°C. The compound of formula (IIIb) is isolated using a solvent selected from MDC and chlroroform, and most preferably using MDC.

Compound of formula (IIIb) is oxidized to 3-acetylbenzaldehyde of formula (II). The oxidation is carried out using suitable oxidizing agents like manganese based or chromium based oxidizing agents like potassium permanganate (KMnO4), potassium dichromate (K2Cr2O7), Johns’s reagent, pyridinium chlorochromate (PCC), Manganese dioxide (MnO2). However, it is understood here that the oxidation using manganese based or chromium based oxidizing agents is carried out at 0-100°C and in a solvent selected from Toluene, chloroform and MDC.

In one more embodiment of the present invention, the reaction may also be carried out using other oxidizing methods such as Swern Oxidation. The reaction is carried out using oxalyl chloride and DMSO in MDC as a solvent. The reaction is carried out at low temperature -70 to -50°C, preferably at -60 to -55°C.

In further one more embodiment of the present invention, the reaction is carried out in presence of sodium hypochlorite solution in presence of 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) as a catalyst. The reaction proceeds in a solvent selected from hydrocarbon solvent and halogenated solvent.

The hydrocarbon solvent is selected from hexane, cyclohexane and toluene. The halogenated solvent is selected from chloroform and methylene dichloride. The reaction is carried out in the temperature range from 0°C to -20°C.

It is understood, however, that the oxidation reaction may also be carried out using peroxy reagents such as hydrogen peroxide (H2O2), Sodium hypochlorite (NaOCl), Sodium hypobromide (NaOBr) optionally in presence of suitable catalyst like sodium tungstate and Ferric dodacane sulfonate.
EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 1-[3-(chloromethyl)phenyl]ethanone

Aluminium chloride (390 g) was added to chloroform (500 ml) under nitrogen atmosphere and dry environment to form a reaction mixture. The reaction mixture was stirred at 20-30°C for 15 minutes and gradually cooled to 5-10°C. Acetophenone (100 g) was gradually added to the reaction mixture and maintained at 10-30°C. The reaction mixture was cooled to 0-5°C and paraformaldehyde (63 g) was added in single lot. The reaction mass was stirred for 15 minutes at 0-5°C. The temperature was then raised to 25-35°C and the mixture was stirred for 1-2 hours. The reaction mixture was slowly added to water-ice mixture (800 ml). The aqueous and organic layers were separated and the chloroform layer was washed with sodium carbonate solution (250 ml x 2). Chloroform was evaporated under reduced pressure at 30-50°C to obtain 1-[3-(chloromethyl)phenyl]ethanone (141 g) as an oil which was purified by high vacuum distillation thereby obtaining said oil having purity of about 98.5%.

Example 2
Preparation of 1-[3-(chloromethyl)phenyl]ethanone
Aluminium chloride (3.9 kg) was added to chloroform (4 Lit) under nitrogen atmosphere and dry environment to form a reaction mixture. The mixture was stirred at 20-30°C for 15 minutes and gradually cooled to 5-10°C. Acetophenone (1 kg) was gradually added to the reaction mixture and maintained at 10-30°C. The mixture was cooled to 0-5°C and paraformaldehyde (625 g) was added in single lot. The reaction mixture was stirred for 15 minutes at 0-5°C and subsequently raised to 25-35°C followed by stirring for 1-2 hours. The reaction mass was slowly added to water-ice mixture (8 lit). The aqueous and organic layers were separated and the chloroform layer was washed with sodium carbonate solution (2.5 lit x 2). Chloroform was evaporated under reduced pressure at 30-50°C to get 1-[3-(chloromethyl)phenyl]ethanone (1.4 kg) as oil which was purified by high vacuum distillation. It was observed that the boiling point was110-115°C (at 1mm Hg).
Example 3
Preparation of 1-[3-(chloromethyl)phenyl]ethanone
Aluminium chloride (11.7 kg) was added to chloroform (12 Lit) under nitrogen atmosphere and dry environment to form a reaction mixture. The mixture was stirred at 20-30°C for 15 minutes and gradually cooled to 5-10°C. Acetophenone (3 kg) was gradually added to the reaction mixture and maintained at 10-30°C. The mixture was cooled to 0-5°C and paraformaldehyde (1.875 kg) was added in single lot. The reaction mixture was stirred for 15 minutes at 0-5°C. Temperature was raised to 25-35°C and the mixture was stirred for 1-2 hours. The reaction mixture was slowly added to water-ice mixture (24 lit). The aqueous and organic layers were separated and the chloroform layer was washed with sodium carbonate solution (7.5 lit x 2). Chloroform was evaporated under reduced pressure at 30-50°C to get 1-[3-(chloromethyl)phenyl]ethanone (4.1 kg) as an oil which was purified by high vacuum distillation to obtain purity of about 99% which was further analyzed to obtain the following values-
NMR (CDCl3) (at 300 Mz) d: 2.50 (3H, s), 4.55 (2H, s), 7.36-7.47 (1H, t), 7.54-7.62 (1H, d), 7.85-7.90 (1H, d), 7.95 (1H, s)

Example 4
Preparation of 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride
Hexamine (60 g) was charged to chloroform (300 ml) and stirred at 20-30°C for 30 minutes to obtain a reaction mixture. The reaction mixture was heated to 50-60°C and stirred for further 30 minutes. In next step, 1-[3-(chloromethyl)phenyl]ethanone (50 g) as obtained in Example 2 was added in single lot. The reaction was maintained at reflux for 2 hours. The reaction mixture was cooled at 20-30°C and stirred for 2 hours. The suspension was filtered and washed with chloroform (300 ml) to obtain 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone hydrochloride which was dried at 30-40°C under vacuum for 5 hours to get dry weight of 78 g.

Example 5
Preparation of 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride
Hexamine (1.2 kg) was charged to chloroform (6 lit) and stirred at 20-30°C for 30 minutes to obtain a reaction mixture. The reaction mixture was heated to 50-60°C and stirred for further 30 minutes. 1-[3-(chloromethyl)phenyl]ethanone (1 kg) as obtained in example (2) was added in single lot. The reaction was maintained at reflux for 2 hours. The reaction mass was cooled at 20-30°C and stirred for 2 hours thereby obtaining a suspension. The suspension was filtered and washed with chloroform (500 ml) thereby obtaining 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone hydrochloride salt which was dried 30-40°C under vacuum for 5 hours to get dry weight of 1.75 kg which was further analyzed to obtain following values-
NMR (DMSO) (at 300 Mz) d: 2.65 (3H, s), 4.24 (2H, s), 4.42-4.61 (6H, q), 5.15 (6H, s), 7.65-7.71 (1H, t), 7.77-7.79 (1H, d), 8.08 (1H, s), 8.09-8.12 (1H, d).

Example 6
Preparation of 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride
Hexamine (3.6 kg) was charged to chloroform (18 lit) and stirred at 20-30°C for 30 minutes to obtain a reaction mixture. The reaction mixture was heated to 50-60°C and stirred for further 30 minutes. Further, 1-[3-(chloromethyl)phenyl]ethanone (3 kg), as obtained in example (1), was added in single lot. The reaction mixture was then maintained at reflux for 2 hours. The reaction mass was cooled at 20-30°C and stirred for 2 hours to obtain a suspension. In final step, the suspension was filtered and washed with chloroform (1.5 l) thereby obtaining 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone hydrochloride salt which was dried at 30-40°C under vacuum for 5 hours to get dry weight of 4.7 kg.

Example 7
Preparation of 3-acetylbenzaldehyde
Acetic acid solution prepared by addition of acetic acid (500 ml) with water (500 ml) was heated to 80-85°C. 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride (100 g) as obtained in example (4) was added lot wise over 30 minutes to form a reaction mixture. The reaction mixture was stirred at 80-85°C for 1 hour. The reaction mixture was cooled to 25-30°C and water (500 ml) and MDC (1 L) was added to the reaction mixture. The layers were separated and aqueous layer was again extracted with MDC (1 L). All MDC layers were treated with 10% sodium bicarbonate solution (1 L) and stirred for another 30 minutes and MDC layers were separated and dried over sodium sulfate (10 g) for 30 minutes. MDC was distilled under vacuum to get 3-acetylbenzaldehyde (22 gm) as oil which was purified by high vacuum distillation to obtain a purity of about 97.5%

Example 8
Preparation of 3-acetylbenzaldehyde
Acetic acid solution prepared by addition of acetic acid (1.25 l) with water (3.75 l) was heated to 80-85°C. 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride (1 kg) as obtained in example (5) was added lot wise over 30 minutes. Stir the reaction mixture was stirred at 80-85°C for 1 hour. The reaction mixture was cooled to 25-30°C and water (2.5 l) and MDC (5 L) were added to the reaction mixture. The layers were separated and aqueous layer was again extracted with MDC (5 L). All MDC layers were treated with 10% sodium bicarbonate solution (2.5 L) and stirred for another 30 minutes and subsequently MDC layers were separated and dried over sodium sulfate (100 g) for 30 minutes. Finally, MDC was distilled under vacuum to get 3-acetylbenzaldehyde (240 gm) which was purified by high vacuum distillation at a boiling point of about 100-105°C (at 1mm Hg).

Example 9
Preparation of 3-acetylbenzaldehyde
Acetic acid solution prepared by addition of acetic acid (3.75 l) with water (11.25 l) was heated to 80-85°C. Subsequently, 1-[3-(hexamethylenetetraminemethyl)phenyl]ethanone chloride (3 kg) as obtained in example (6) was added lot wise over 30 minutes. The reaction mixture was stirred at 80-85°C for 1 hour. The reaction mixture was cooled to 25-30°C and water (7.5 l) and MDC (15 L) was added to the reaction mixture. The layers were separated and aqueous layer was again extracted with MDC (15 L). All MDC layers were treated with 10% sodium bicarbonate solution (7.5 L) and stirred for another 30 minutes. MDC layers were separated and dried over sodium sulfate (300 g) for 30 minutes. Finally, MDC was distilled under vacuum to get 3-acetylbenzaldehyde (800 gm) as oil which was purified by high vacuum distillation followed by analysis thereof to obtain following data-
NMR (CDCl3) (at 300 Mz) d: 2.62 (3H, s), 7.56-7.62 (1H, t), 8.00-8.04 (1H, d), 8.14-8.18 (1H, d), 8.45 (1H, S), 10.03 (1H, s)

Example 10
Preparation of 1-[3-(hydroxymethyl)phenyl]ethanone
Sodium carbonate solution was prepared by dissolving sodium carbonate (4 g) in water (40 ml). Further, 1-[3-(chloromethyl)phenyl]ethanone (5 g) as obtained in example (1) was added to the sodium carbonate solution to form a reaction mixture and the reaction mixture was stirred vigorously. The reaction mixture was heated to 100°C and maintained till the reaction completion. The reaction mixture was cooled to 25-30°C and MDC (15 ml) was added after completion of the reaction followed by stirring thereof for 30 minutes. The layers were separated and MDC layer was washed with water (10 ml) and brine solution (10 ml). Finally, MDC layer was distilled under reduced pressure to yield 1-[3-(hydroxymethyl)phenyl]ethanone (4 g) as oil which was analyzed to obtain following values-.
NMR (CDCl3) d: 2.52 (3H, s), 2.87 (1H, bs), 4.59 (2H, s), 7.30-7.40 (1H, t), 7.45-7.50 (1H, d), 7.73-7.79 (1H, d), 7.84 (1H, s).

Example 11
Preparation of 1-[3-(hydroxymethyl)phenyl]ethanone
Sodium carbonate solution was prepared by dissolving sodium carbonate (44.8 g) in water (448 ml). 1-[3-(chloromethyl)phenyl]ethanone (56 g) as obtained in example (3) was added to the sodium carbonate solution and the reaction mixture was stirred vigorously. The reaction mixture was heated to 100°C and maintained till the reaction completion. The reaction mixture was cooled to 25-30°C and MDC (168 ml) was added followed by stirring the reaction mixture for 30 minutes. The layers were separated and MDC layer was washed with water (112 ml) and brine solution (112 ml). Finally, MDC layer was distilled under reduced pressure to yield 1-[3-(hydroxymethyl)phenyl]ethanone (46 g) as oil having purity of about 97%.

Example 12
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (500 g) as obtained in example (11) was added to nitric acid solution prepared by dissolving HNO3 (126 g) in water (1 L). Sodium nitrite (12g) was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 90-95°C for 3 hours and cooled to room temperature thereby obtaining. 3-acetylbenzaldehyde which was extracted with MDC (2x500ml). The organic layer was washed with saturated sodium bicarbonate (500 ml) followed by water (500 ml). The organic layer was dried over sodium sulfate (100 g) which was evaporated to yield 3-acetylbenzaldehyde (320 g) as viscous oil which was purified by high vacuum distillation.

Example 13
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (50 g) as obtained in example (11) was dissolved in Toluene (1 L) at 25-30°C to get a clear solution. Activated MnO2 (150 g) was added to the solution and the reaction mass was refluxed for 28 hours. The reaction mass was cooled to 25-30°C and filtered. The filtrate was evaporated to get 3-acetylbenzaldehyde (41 g) which was purified by high vacuum distillation at a boiling point of about 100-105°C (at 1mm Hg).

Example 14
Preparation of 3-acetylbenzaldehyde
Pyridinium chlorochromate (8.7 g) was added to the solution of 1-[3-(hydroxymethyl)phenyl]ethanone (5 g) as obtained in example (10) in MDC (50 ml) to form a reaction mixture. The reaction mixture was stirred for 2 hours. Subsequently, 1N HCl (50 ml) was added to the reaction mixture and stirred for 30 minutes. MDC layer was washed with water (2x50ml). MDC layer was washed with saturated sodium bicarbonate (50 ml) and dried over sodium sulfate (5 g). Finally, MDC layer was evaporated to yield 3-acetylbenzaldehyde (4.8 g) as viscous oil which was purified by high vacuum distillation to obtain purity of about 97%.

Example 15
Preparation of 3-acetylbenzaldehyde
Oxalyl chloride (12.68 gm) was added to mixture of DMSO (15.57 g) and MDC (100 ml) to form a reaction mixture. The reaction mixture was cooled to -55 to -600C. Subsequently, 1-[3-(hydroxymethyl)phenyl]ethanone (10 g) dissolved in MDC (50 ml) was added to the reaction mixture and further stirred at -60° for 30 minutes. Triethyl amine (38.87 g), was then charged to reaction mixture at -55 to -600C. The reaction mixture was then gradually warmed to 25-30°C and added into water (250 ml). The aqueous layer was extracted with MDC (100 ml). All the MDC layers were combined and washed with 2N HCl (100 ml) and then saturated with sodium bicarbonate (100 ml). Finally, MDC layer was dried over sodium sulfate (20 g) and evaporated to get 3-acetylbenzaldehyde (9.52 g) in an oil form which was purified by high vacuum distillation to obtain purity of about 97.5%.

Example 16
Preparation of 3-acetylbenzaldehyde
Triethylamine (34 g) was added to a suspension of potassium permanganate (100 g), Chloroform (1L) and water (50 ml) at 25-30°C to form a reaction mixture and the reaction mixture was cooled to 0-5°C. 1-[3-(hydroxymethyl)phenyl]ethanone (50 g) as obtained in example (11) was added to the reaction mixture. 6M Sulfuric acid (600 ml) was added drop wise to the reaction mass over 40 minutes. The temperature was maintained between 0-5°C. The reaction mixture was filtered and layers were separate followed by washing with water (500 ml) and saturated with sodium bicarbonate (500 ml). The chloroform layer was dried over sodium sulfate and evaporated to get 3-acetylbenzaldehyde (38.5 g) as viscous oil which was purified by high vacuum distillation to obtain purity of about 98%.

Example 17
Preparation of 3-acetylbenzaldehyde
Triethylamine (6.73 g) was added to a suspension of potassium permanganate (13.69 g), Chloroform (10 ml) and water (10 ml) at 0-5°C. 1-[3-(hydroxymethyl)phenyl]ethanone (10 g) as obtained in example (11) was added to the reaction mixture. 2.5M Sulfuric acid (133 ml) was added drop wise to the reaction mixture over 40 minutes. The temperature was maintained between 0-5°C. The reaction mixture was filtered and layers were separated. Chloroform layer was washed with water (100 ml) and saturated with sodium bicarbonate (100 ml). The chloroform layer was dried over sodium sulfate and evaporated to get 3-acetylbenzaldehyde (9.8 g) as viscous oil which was purified by high vacuum distillation to obtain purity of about 97.9%

Example 18
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (5g) as obtained in example (11) was added to ferric dodecanesulfonate (0.2g) to form a reaction mixture. The reaction mixture was heated to 90°C and 30% H2O2 (22.5mL) was added drop-wise. The reaction mixture was stirred at 900C for 6 h followed by adding Water (50 ml) and toluene (50 ml) and stirring at 25-300C for 30 minutes. The layers were separated and aqueous layer was back extracted with toluene (50 ml). The combined toluene layer was washed with saturated sodium bicarbonate (50 ml) and distilled to get 3-acetylbenzaldehyde (4.5 g) as viscous oil which was purified by high vacuum distillation to obtain purity of about 98%.

Example 19
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (5g) as obtained in example (11) was added to mixture of sodium tungstate dihydrate (0.1 g) and tetrabutylammonium bromide (0.2 gm). The reaction mixture was heated to 900C. 50% H2O2 was added dropwise to the reaction mixture, over a period of 2hrs. The resulting mixture was stirred at 90°C for 5 h. The reaction was saturated sodium thiosulfate solution (50 ml) and toluene (50 ml) was added and stirred at 25-300C for 30 minutes. Layers were separated and toluene layer was washed with saturated sodium bicarbonate (50 ml) and distilled to get 3-acetylbenzaldehyde (4.2 g) as viscous oil. The product obtained was purified by high vacuum distillation.

Example 20
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (36 g) as obtained in example (11) was added to methylene dichloride (180 ml) and the reaction mixture was stirred for 15-20 minutes at 25-30°C. Potassium bromide solution was prepared by dissolving 29 gm of potassium bromide in water (43 ml). The potassium bromide solution was added to the reaction mass at 25-30°C. The reaction mass was cooled to -15 to -10°C with continuous stirring. TEMPO catalyst (0.711 g) was added to the reaction mass at -15 to -10°C.
Sodium hypochlorite solution was prepared by mixing sodium hypochlorite (8% solution in water) (290 gm) with sodium bicarbonate (36 g) and stirred for 30 minutes. The above sodium hypochlorite solution was gradually added to the reaction mass at -15 to -10°C in 1 to 2 hours. The reaction mass was maintained at -10 to -2°C for 1 hour. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene dichloride. All methylene dichloride layers were combined, washed with sodium thiosulfate (10% solution) and distilled under vacuum at 30 to 35°C to get 3-acetylbenzaldehyde (32 g) as viscous oil.

Example 21
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (500 g) as obtained in example (11) was added to methylene dichloride (2500 ml) and the reaction mixture was stirred for 15-20 minutes at 25-30°C. Potassium bromide solution was prepared by dissolving 402.7 gm of potassium bromide in water (598 ml). The potassium bromide solution was added to the reaction mass at 25-30°C.The reaction mass was cooled to -15 to -10°C with continuous stirring. TEMPO catalyst (9.9 g) was added to the reaction mass at -15 to -10°C. Sodium hypochlorite solution was prepared by mixing sodium hypochlorite (8% solution in water) (4028 gm) with sodium bicarbonate (500 g) and stirred for 30 minutes. The above sodium hypochlorite solution was gradually added to the reaction mass at -15 to -10°C in 1 to 2 hours. The reaction mass was maintained at -10 to -2°C for 1 hour. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene dichloride. All methylene dichloride layers were combined, washed with sodium thiosulfate (10% solution) and distilled under vacuum at 30 to 35°C to get 3-acetylbenzaldehyde (482 g) as viscous oil.

Example 22
Preparation of 3-acetylbenzaldehyde
1-[3-(hydroxymethyl)phenyl]ethanone (25 kg) as obtained in example (11) was added to methylene dichloride (125 L) and the reaction mixture was stirred for 15-20 minutes at 25-30°C. Potassium bromide solution was prepared by dissolving 20 kg of potassium bromide in water (29.86 L). The potassium bromide solution was added to the reaction mass at 25-30°C. The reaction mass was cooled to -15 to -10°C with continuous stirring. TEMPO catalyst (0.455 kg) was added to the reaction mass at -15 to -10°C. Sodium hypochlorite solution was prepared by mixing sodium hypochlorite (8% solution in water) (201.3 kg) with sodium bicarbonate (25 kg) and stirred for 30 minutes. The above sodium hypochlorite solution was gradually added to the reaction mass at -15 to -10°C in 1 to 2 hours. The reaction mass was maintained at -10 to -2°C for 1 hour. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene dichloride. All methylene dichloride layers were combined, washed with sodium thiosulfate (10% solution) and distilled under vacuum at 30 to 35°C to get 3-acetylbenzaldehyde (23 kg) as viscous oil.

Example 23
Preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone
7-chloroquinaldine (4 g) was added to 3-acetylbenzaldehyde (2 g), as prepared in example 17, followed by adding acetic anhydride (2 ml) and toluene (6 ml) to form a reaction mixture which was subsequently stirred. The reaction mixture was heated to 100 - 110°C for 12 hours which was gradually cooled to a room temperature. Further, the reaction mixture was cooled to 5-10°C and maintained for 1 hour. The product so obtained was filtered and suck dried well to obtain a wet cake which was added to heptane (15 ml) and stirred for 2 hours. The product was filtered and washed with heptane (5 ml) and suck dried to obtain pure 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl] ethanone (3.1 g) as light yellow powder having purity of about 97%.

Example 24
Preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone
7-chloroquinaldine (120 g) was added to 3-acetylbenzaldehyde (100 g), as prepared in example 3, to form a reaction mixture. Acetic anhydride (300 ml) and toluene (300 ml) was added to the reaction mixture and stirred. The reaction mixture was heated to 100 - 110°C for 15 hours, and gradually cooled to a room temperature. Further, the reaction mixture was cooled to 5-10°C and maintained for 1 hour to obtain a product. The product obtained was filtered and suck dried well to obtain a wet cake. The wet cake was added to heptane (300 ml) and stirred for 2 hours. Finally, the product was filtered and washed with heptane (100 ml) and suck dried to get pure 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl] ethanone (170 g) as light yellow powder having purity of about 98.09% which was further analyzed to obtain following data-
NMR (CDCl3) (at 300 Mz) d: 2.60 (3H, s), 7.33-7.46 (3H, m), 7.56-7.72 (3H, m), 7.75-7.77 (1H, d), 7.83-7.87 (1H, d), 8.00-8.07 (2H, m), 8.15 (1H, s).

Example 25
Preparation of 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]ethanone
7-chloroquinaldine (500 g) was added to 3-acetylbenzaldehyde (25 g), as prepared in example 16, to obtain a reaction mixture. Acetic anhydride (750 ml) and toluene (750 ml) was added to the reaction mixture and stirred. The reaction mixture was heated to 100 - 110°C for 15 hours, and said mixture was gradually cooled to room temperature. Further the reaction mass was cooled to 5-10°C and maintained for 1 hour to obtain a product. The product obtained was filtered and suck dried well to obtain a wet cake. The wet cake was added to heptane (1000 ml) and stirred for 2 hours. Finally, the product was filtered and washed with heptane (100 ml) and suck dried to get pure 1-[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl] ethanone (426 g) as yellowish white powder having melting point: 171°C; and purity of about 99%.