Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula (I).

The present invention relates to a improved process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I having purity greater than 99%.

BACKGROUND OF THE INVENTION
2-[(4-Bromophenyl)(methoxy)methylene]malononitrile, belongs to aryl substituted activated alkenes or enones compound, mostly employed as an intermediate compound in the manufacturing of various kinase inhibitors drugs like Pirtobrutinib, Ibrutinib, etc., showing anti-cancer activity. Tyrosine kinase inhibitors are drugs that block the action of tyrosine kinases, which are enzymes that control cell growth, division, and signaling. TKIs are used to treat a variety of cancers.
Because of its importance in cancer therapy, it is extremely attractive to pharmaceutical manufacturers to develop a cost-effective, high-yield and environmentally friendly synthesis method of anti-cancer drug intermediates. Currently, in the synthesis process of anti-cancer drugs, the synthesis efficiency and cost of key intermediates are one of the main factors in the preparation cost. Conventional synthetic methods typically involve multiple steps of reactions and require the use of expensive and environmentally-costly reagents and solvents, which results in inefficiency of the overall synthetic process, increased costs, and potential harm to the environment.

Therefore, it is important to provide an economical process by which 2-[(4-bromophenyl)(methoxy)methylene]malononitrile can be prepared to make easy manner in the required quality with better yields as per the pharmaceutical product’s regulatory guidelines.

The common disadvantages of the known procedures found in prior art references, US 9796716, US 10695323, WO 2005005430 A2, are that the process are carried out at an uneconomical and dangerous industrial procedure and require extra equipment and were carried out at an extreme reaction condition as described above.

It is well known fact that, the active pharmaceutical ingredients (APIs) are clearly dependents of the intermediates compounds which are used in the reaction and always leads to provide better productivity in the final stage. The use of economically produced intermediates will result in the production of API at an economically affordable condition.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile of compound of Formula I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide the improved process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I.

In another objective, the present invention is to provide a method for purification 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I having purity greater than 99%.

In yet another objective, the present invention is to provide a process for preparation 2-[(4-bromophenyl)(hydroxy)methylene]malononitrile of compound of Formula II.

SUMMARY OF THE INVENTION
The present invention is to provide a cost effective, novel and an efficient process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I;

In one aspect, the present invention is to provide a process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I

which comprises of:
a) chlorination of 5-bromobenzoic acid compound of Formula IV

with oxalyl oxylyl chloride in the presence of a dichloromethane to give in-situ compound of 5-bromobenzoyl chloride compound of Formula III;

b) nucleophilic addition of the in-situ compound of Formula (III) obtained in step (a) with malononitrile in the presence of a base and tetrahydrofuran to give 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula (II); and

c) methylation of Formula (II) obtained in step (b) by using Dimethyl sulphate in the presence of Sodium carbonate and 1,4-Dioxane to give 2-[(4-Bromophenyl)(methoxy)methylene]malononitrile compound of Formula-I; and

d) optionally purifying the step (c) compound to obtain high pure compound of Formula I.

In another aspect, the present invention is to provide an improved process for the preparation of 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula II

which comprises of:
a) chlorination of 5-bromobenzoicacid compound of Formula IV.

with oxalyl chloride in the presence of a dichloromethane to give in-situ compound of 5-bromobenzoylchloride compound of Formula III; and

b) nucleophilic addition of the in-situ compound of Formula (III) obtained in step (a) with malononitrile in the presence of a base and tetrahydrofuran to give 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula (II).

DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification have the meanings given below:

Solvents used throughout the invention is selected from the group consisting of hydrocarbon solvents such as pentane, hexane, cyclohexane, heptane, xylene, toluene; alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, amide solvent such as dimethyl sulfate, dimethylacetamide, dimethylformamide, formamide, N-Methyl formamide, chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride, organosulfur solvent such as dimethyl sulfoxide, dimethyl sulfone, acetic acid, water, 1,4-dioxane and its mixture thereof.

Base used throughout the invention is selected from the group consisting of include, but are not limited to alkylmetal base such as methyllithium, n-butyllithium, tertbutyl lithium, sec-butyllithium, phenyl lithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, diisopropylamine, lithium diisopropylamide, lithium diethylamide or lithium dicyclohexylamide. sodium hydride, potassium hydride, NaOPt, n-butyllithium, tert-butyllithium, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, sodium bicarbonate, ammonium hydroxide, sodium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium iodide, rubidium hydroxide, trimethylamine, Sodium-tert-butoxide, dimethyl sulfate or cesium hydroxide.

Reducing agents used throughout the invention is selected from the group consisting of metal and non-metallic reducing agents like such as sodium borohydride, lithium borohydride, aluminum borohydride, triethyl amine, di-ethylamine, borane, di-borane, hydrazine, methylhydrazine, potassium borohydride, sodium amino di-boronate, oxalic acid, formic acid, oxalyl chloride, thionyl chloride, ethanoyl chloride, benzoyl chloride or activated .

The process of the present invention is advantageous from environmental point of view, economical from time duration point of view, safe from the avoiding the hazardous chemical point of view and advancement in view of good yield i.e., more than 70% and better purity i.e., more than 99%.

Accordingly, the present invention provides a process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I.

The main embodiment of the present invention provides a process for the preparation of 2-[(4-bromophenyl)(methoxy)methylene]malononitrile compound of Formula I which is outlined in below scheme I:

Scheme I
In step a), chlorination of 5-bromobenzoic acid compound of Formula IV with oxalyl chloride in the presence of a dichloromethane to give in-situ compound of 5-bromo benzoyl chloride compound of Formula III;

The reaction is carried out at a temperature range of 15-50 oC for 2-8 hours. Preferably at a temperature in the range from 20-40 oC for a duration of 4-6 hours.

In step b), nucleophilic addition of the in-situ compound of Formula (III) obtained in step (a) with malononitrile in the presence of a base and tetrahydrofuran to give 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula (II);

The reaction is carried out at a temperature range of 15-50 oC for 2-8 hours. Preferably at a temperature in the range from 20-40 oC for a duration of 4-6 hours.

In step c), methylation of Formula (II) obtained in step (b) by using Dimethyl sulphate in the presence of Sodium carbonate and 1,4-Dioxane to give 2-[(4-Bromophenyl)(methoxy)methylene]malononitrile compound of Formula-I;

The reaction is carried out a temperature range of 70-130°C for 20-28 hours. Preferably at a temperature in the range from 85-110 oC for a duration of 22-26 hours.

In step d), optionally purifying the step (c) compound to obtain high pure compound of Formula I;

In another embodiment, the present invention provides an improved process for the preparation of 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula II which is outlined in below scheme II:

Scheme II
In step a), chlorination of 5-bromobenzoic acid compound of Formula IV with oxalyl chloride in the presence of a dichloromethane to give in-situ compound of 5-bromo benzoyl chloride compound of Formula III;

The reaction is carried out at a temperature range of 15-50 oC for 2-8 hours. Preferably at a temperature in the range from 20-40 oC for a duration of 4-6 hours.

In step b), nucleophilic addition of the in-situ compound of Formula (III) obtained in step (a) with malononitrile in the presence of a base and tetrahydrofuran to give 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula (II);

The reaction is carried out at a temperature range of 15-50 oC for 2-8 hours. Preferably at a temperature in the range from 20-40 oC for a duration of 4-6 hours.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1: Process for the preparation of [2-[(4-Bromophenyl) (hydroxy)methylene] malononitrile (II)
A stirred solution of Dichloromethane (4000 mL), Dimethyl formamide (9.44 grams, 0.052 mole) and 4-Bromobenzoic acid (500.0 grams, 2.48 mole) were maintained at ambient temperature for 15 mins, Then oxalyl chloride (474.0 grams, 3.727 mole) was added dropwise at 10-15 °C under nitrogen atmosphere. The resulting mixture is stirred for 4 hours at ambient temperature. The mixture is concentrated under reduced pressure to get the crude. This crude was dissolved in Tetrahydrofuran (500 mL) and adjusted the pH 6-7 by using N, N-Diisopropylethyl amine (70.0 mL) at 10-15 °C under nitrogen atmosphere.
In other RBF, Sodium-tert-butoxide (716.4 grams, 7.455 mol) in Tetrahydrofuran (2500 mL) were stirred at ambient temperature for 15 mins. Solution of malononitrile (246. grams, 3.727 mol) in Tetrahydrofuran (500 mL) is added dropwise into a stirred suspension at 10-15 °C under Nitrogen atmosphere. The mixture is then stirred for 60 minutes at 10-15 °C. Then the crude 5-bromobenzoyl chloride in Tetrahydrofuran (500 mL) is added to the reaction mixture dropwise at 0-10 °C. The reaction is stirred for 2 hrs at 10-15 °C. Then it was acidified with 1N HCl to pH 2. This mixture was extracted with ethyl acetate (2 x 500 mL) and dried over sodium sulfate. The ethyl acetate layer was distilled off completely under reducing pressure at below 55 °C. Cooled the resultant crude material to ambient temperature and dissolved in Isopropyl acetate (2000 mL), stirred for 15 mins. Heated the mass to 45-50 °C for 30 mins and slowly cooled the reaction mass to 10-15 °C. Stirred the reaction mass for 2 hrs at the same temperature and filtered the solid, washed with chilled Isopropyl acetate (250.0 mL). Dried the material at below 60 °C for 8-10 hrs to get 452.0 grams of 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile (II) (Yield: 73.0 %), Purity by HPLC: 98.0 %.

Example 2: Process for the preparation of [2-[(4-Bromophenyl) (hydroxy)methylene] malononitrile (II)
A stirred solution of Dichloromethane (4000 mL), Dimethyl formamide (9.44 grams, 0.052 mole) and 4-Bromobenzoic acid (500.0 grams, 2.48 mole) were maintained at ambient temperature for 15 mins, Then oxalyl chloride (474.0 grams, 3.727 mole) was added dropwise at 10-15 °C under nitrogen atmosphere. The resulting mixture is stirred for 4 hours at ambient temperature. The mixture is concentrated under reduced pressure to get the crude. This crude was dissolved in Tetrahydrofuran (500 mL) and adjusted the pH 6-7 by using N, N-Diisopropylethyl amine (70.0 mL) at 10-15 °C under nitrogen atmosphere.

Sodium hydride (320.6grams, 8.33mol 60 % in oil) was suspended in Tetrahydrofuran (2500 mL) were stirred at ambient temperature for 15 mins under Nitrogen atmosphere. Solution of malononitrile (246. grams, 3.727 mol) in Tetrahydrofuran (500 mL) was added dropwise into a stirred suspension at 10-15 °C under Nitrogen atmosphere. The mixture was then stirred for 60 mins at 10-15 °C under Nitrogen atmosphere. Then the crude 5-bromobenzoyl chloride in Tetrahydrofuran (500 mL) is added into the reaction mixture dropwise at 10-15 °C. The reaction is stirred for 2 hrs at 10-15 °C. Then it was acidified with 1N Hydrochloric acid solution to pH 1-2. This mixture was extracted with Ethyl acetate (2 x 500 mL) and dried over sodium sulfate. The ethyl acetate layer was distilled off completely under reducing pressure at below 55 °C. Cooled the resultant crude material to ambient temperature and dissolved in Isopropyl acetate (2000 mL), stirred for 15 mins. Heated the mass to 45-50 °C for 30 mins and slowly cooled the reaction mass to 10-15 °C. Stirred the reaction mass for 2 hrs at the same temperature and filtered the solid, washed with chilled Isopropyl acetate (250.0 mL). Dried the material at below 60 °C for 8-10 hrs to get 527.0 grams of 2-[(4-Bromophenyl)(hydroxy)methylene]-malononitrile (II) (Yield: 85.0 %), Purity by HPLC: 98.0 %.

Example 3: Process for the preparation of 2-[(4-Bromophenyl)(methoxy)methylene] malononitrile (I)
A solution of 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile (II) (500.0 grams; 2.0075 mole) was added into 1,4-Dioxane (2000 mL) at ambient temperature. Then added Sodium carbonate (745.0 grams; 7.0349 mole) into the mass and stirred for 15 mins at ambient temperature. Dimethyl sulphate (1266.0 grams; 10.0375 mole) was added dropwise at 10-15 °C. This reaction mass was heated to 70-75 °C for 2 hrs and cooled to the ambient temperature. In other RBF, process water (5000 mL) was taken and cooled to 10-15 °C. Reaction mass was slowly added into the precooled water and stirred for 2 hrs at 10-15 °C. Filtered the mass and washed with pre-cooled process water (500 mL). Dichloromethane (5000.0 mL) was added to it, stirred for 30 mins at ambient temperature. Heated the mass to 35-40 °C to get clear solution. To this, added activated carbon (50.0 grams) and stirred for 30 mins. Filtered the mass through celite and washed the celite bed with Dichloromethane (250.0 mL). Evaporated the filtrate completely at below 40 °C under reduced pressure. To the obtained crude, added Methanol (1.5 L) and heated to 60-65 °C and stirred for 1 hr. This mixture was cooled 10-15 °C and stirred for 2 hrs. Filtered the solid and washed with Pre-cooled Methanol (250.0 mL). Dried the material at 60-65 °C for 8-10 hrs to get 378.0 grams of 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile (I) (Yield: 72 %), Purity by HPLC: 99.0 %.
Advantages of the present invention:
1. The present invention is robust, echo friendly, safe and commercially feasible process.
2. The processes disclosed in prior art references involved the use of toxic reagents and were having a greater number of steps. Where as in the present invention non-toxic reagents are used and involved less number of steps.
3. All reagents used in the present invention are commercially available and less expensive and hence the process is economically viable.
4. Present invention involved with lesser work up time, and all intermediate crudes proceeded for next stages were without isolation compared to prior art processes.
5. Good yield & purity is observed and load on equipment’s & instruments is also less on commercial point of view when compared to prior art processes.
, Claims:1. An improved process for the process of the preparation of 2-[(4-bromophenyl) (methoxy)methylene]malononitrile compound of Formula I

which comprises of:
a) chlorination of 5-bromobenzoic acid compound of Formula IV

With oxalyl chloride in the presence of a dichloromethane to give in-situ compound of 5-bromobenzoyl chloride compound of Formula III;

b) nucleophilic addition of the in-situ compound of Formula (III) obtained in step (a) with malononitrile in the presence of a base and tetrahydrofuran to give 2-[(4-Bromophenyl)(hydroxy)methylene]malononitrile compound of Formula (II); and

c) methylation of Formula (II) obtained in step (b) by using Dimethyl sulphate in the presence of Sodium carbonate and 1,4-Dioxane to give 2-[(4-Bromophenyl)(methoxy)methylene]malononitrile compound of Formula-I; and

d) optionally purifying the step (c) compound to obtain high pure compound of Formula (I).

2. The process as claimed in stage b of claim 1, wherein base used for nucleophilic addition is selected from the group consisting of bases like Sodium-tert-butoxide, or sodium hydride.

3. The process as claimed in stage b of claim 1, wherein base used for nucleophilic addition is preferably Sodium-tert-butoxide or Sodium hydride.