WO2012131699A1

WO2012131699A1 - Process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate

Info

Publication number: WO2012131699A1
Application number: PCT/IN2011/000721
Authority: WO
Inventors: Mahesh Bhagoji Dalvi; Rajesh Shashikant Kenny; Pradeep Kisan Tarade; Dattatray Krishna CHINCHKAR
Original assignee: Neon Laboratories Ltd.
Priority date: 2011-03-30
Filing date: 2011-10-18
Publication date: 2012-10-04

Abstract

The invention discloses a novel process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate via formation of aryl dimethylcarbamate which can be easily obtained from diaryl carbonate and dimethylamine.

Description

"PROCESS FOR PREPARATION OF HIGHLY PURE 3- DIMETHYLAMINOPHENYL DIMETHYLCARBAMATE"

TECHNICAL FIELD:

The present invention relates to a novel process for preparation of highly pure 3- dimethylaminophenyl dimethylcarbamate of formula (I), an intermediate of neostigmine, from diaryl carbonate of formula (II), under mild conditions.

Formula (II) where R_\ is an electron withdrawing group; R₂ and R₃ are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or R₂ and R₃ when placed ortho to each other form benzene ring; R₃ and R4 are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R₃ and R4 together with nitrogen form 3 to 7 members heterocyclic ring.

BACKGROUND AND PRIOR ART:

Neostigmine named chemically 3-[[(dimethylamino)carbonyl]oxy]-N,N,N- trimethylbenzenaminium methyl sulfate is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor. It is used to improve muscle tone in people with myasthenia gravis and routinely, in anesthesia at the end of an operation, to reverse the effects of non-depolarizing muscle relaxants such as Rocuronium and Vecuronium. It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.

Neostigmine has following structure:

Neostigmine was disclosed in the US patent 1905990, where it was obtained by reaction of 3-dimethylaminophenol with N-dimethylcarbamoyl chloride to form 3- dimethylaminophenyl dimethylcarbamate; followed by alkylation of resulting dimethylcarbamate using dimethylsulphate. The process describes benzene as a solvent, and the product is isolated by distillation. The process of distillation is not at all industrially applicable as it is time consuming, and requires high temperature and separate set up. Also the patent does not disclose the purity of 3-dimethylaminophenyl dimethylcarbamate and neostigmine.

The patent GB342237 discloses the preparation of neostigmine by reaction of 3- dimethylaminophenyl chloroformate with dimethylamine to form 3-dimethylaminophenyl dimethylcarbamate; followed by alkylation of resulting dimethylcarbamate with dimethylsulphate. The process describes benzene as a solvent, and the product is isolated by distillation.

3-dimethylaminophenyl chloroformate is moisture sensitive, hazardous and hence requires dry conditions. The process is carried out in benzene and the product is isolated by distillation. More importantly, the patent does not disclose the purity of 3- dimethylaminophenyl dimethylcarbamate and neostigmine.

The European patent EP 193926 discloses the preparation of phenyl carbamates involving reaction of hydroxyphenyl-substituted alkyl amines with appropriate isocyanates or carbamoyl chlorides. The process using isocyanates involves the use of benzene as a solvent. Isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and non-volatile nature. The other alternative reported in this patent is the use of carbamoyl chlorides along with reactive bases like sodium hydride, to prepare the carbamates. The use of a reactive base like sodium hydride on an industrial scale is hazardous and operationally non-user friendly due to its pyrophoric and reactive nature. The US application US20100113819 discloses a method for making carbamates by reacting an amine with an ester-substituted diaryl carbamate. However the method is applicable only for ester-substituted diaryl carbamates and does not teach the preparation of 3-dimethylaminophenyl dimethylcarbamate which does not contain ester group.

The US patent 4315861 discloses a process for preparing carbamic acid phenyl ester by O-acylation of phenolic compounds with N-carbamoyl saccharin derivatives. However the patent does not disclose the source of N-carbamoyl saccharin derivatives and does not teach the preparation of 3-dimethylaminophenyl dimethylcarbamate.

Needless to say it is advantageous to develop a process for preparation of highly pure 3- dimethylaminophenyl dimethylcarbamate, which eliminates the necessity of hazardous substances such as chloroformates, highly toxic reagents such as isocyanates, dry reaction conditions and distillation.

OBJECT OF THE INVENTION:

It is therefore an object of the invention is to overcome or ameliorate atleast one disadvantage of the prior art or to provide a useful alternative.

Another object of the invention is to provide a novel, high yielding process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate which is an intermediate of neostigmine from diaryl carbonate, using mild conditions, avoiding a need of hazardous chemicals and also avoiding purification process such as distillation at high temperature and high vacuum.

Another object of the invention is to provide a novel process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate using easily available starting materials and with easy work-up.

Yet another object of the invention is to provide a concise, commercially viable and industrially applicable process for preparation of highly pure neostigmine methylsulphate having desirable pharmacological activity, broad safety margins, without toxicity or unfavourable side effects. SUMMARY OF THE INVENTION.

In accordance with the above objectives, the present invention provides an economic, industrially feasible and high yielding process for the preparation of highly pure neostigmine intermediate from diaryl carbonate, under mild conditions.

According to one aspect, the present invention provides a process for preparation of 3- dimethylaminophenyl dimethylcarbamate comprising reacting diaryl carbonate with dimethylamine to form aryl dimethylcarbamate; and reacting aryl dimethylcarbamate with 3-dimethylaminophenol.

In another aspect, the present invention provides an alternative process for preparation of aryl dimethylcarbamate comprising reacting dimethylcarbamoyl chloride with a substituted phenol to form an aryl dimethylcarbamate; and reacting aryl dimethylcarbamate with 3-dimethylaminophenol.

In a further aspect, the present invention provides a process for quaternistion of aryl dimethylcarbamate to provide neostigmine.

DETAILED DESCRD7TION OF THE INVENTION:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and material or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specified as follows:

Unless stated to the contrary, any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims. Accordingly, the present invention provides a process to prepare highly pure 3- dimethylaminophenyl dimethylcarbamate of formula (I)

Formula (I)

comprising following steps: a. reacting diaryl carbonate of formula (II) with dimethylamine to form an aryl dimethylcarbamate of formula (III)

Formula (III) where Ri is an electron withdrawing group; R₂ and R₃ are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or R₂ and R₃ when placed ortho to each other form benzene ring; R₃ and R4 are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R₃ and R4 together with nitrogen form 3 to 7 members heterocyclic ring; b. optionally isolating the aryl dimethylcarbamate of formula (III) obtained in the step 'a'; and c. reacting the aryl dimethylcarbamate of formula (III) obtained in the step 'a', with 3- dimethylaminophenol.

Thus the process avoids the use of water sensitive chloroformate.

The process of the present invention is advantageously carried out in one-pot i.e. without isolating aryl dimethylcarbamate of formula (III).

In a preferred embodiment Ri is an electron withdrawing group selected from N0₂, CN or CO-alkyl; R₂ is hydrogen or electron withdrawing group selected from N0₂, CN or CO- alkyl; and R₃ is hydrogen.

The reaction is carried out by reacting bis(4-nitrophenyl) carbonate or bis(2-nitrophenyl) carbonate with dimethylamine to form a 4-nitrophenyl dimethylcarbamate or 2- nitrophenyl dimethylcarbamate respectively. The resulting 4-nitrophenyl dimethylcarbamate or 2-nitrophenyl dimethylcarbamate is reacted with 3- dimethylaminophenol to obtain 3-dimethylaminophenyl dimethylcarbamate.

The reaction of bis(4-nitrophenyl) carbonate or bis(2-nitrophenyl)carbonate with dimethylamine may be carried out at suitable temperature. To minimize the decomposition of products and impurity formation the reaction is carried out at -20°C to 45°C, more preferably at 0° to 35°C. The most preferred reaction temperature is 10°C to 25°C.

The step 'a' of the reaction is preferably carried out in a suitable solvent. The reaction of aryl dimethylcarbamate of formula (III) obtained in the step 'a' with 3- dimethylaminophenol is preferably carried out in presence of a base and a suitable solvent. The base which may be used in the present invention is an inorganic base. Examples of inorganic base include alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide and mixture thereof. Examples of alkali metal carbonate include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate. Examples of alkaline earth metal carbonate include calcium carbonate and magnesium carbonate. Examples of alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate. The examples of alkali metal hydroxide include potassium hydroxide and sodium hydroxide. The preferred base is potassium hydroxide.

The base is conveniently used in an amount, relative to aryl dimethylcarbamate of formula (III), preferably in a range between 0.8 to 2 equivalents, more preferably 1.2 to 1.8 equivalents. The most preferred quantity of the base is 1.4 to 1.6 equivalents.

The suitable solvent used according to the process of the invention in both the steps may be selected from any polar solvent, non polar solvent or mixture thereof. The preferred solvent is toluene.

The reaction of aryl dimethylcarbamate of formula (III) obtained in the step 'a' with 3- dimethylaminophenol may be carried out at 60°C to 145°C, more preferably at 80° to 135°C. The most preferred reaction temperature is 100°C to 125°C.

The resulting 3-dimethylaminophenyl dimethylcarbamate is isolated as a pale yellow oil in 88 - 96% yield with HPLC purity greater than 98%, hence the process avoids the step of distillation which was essentially required for purification in the prior art processes.

In another embodiment, the present invention describes an alternative method for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate of formula (I).

Formula (I)

The process comprises following steps: i. reacting dimethylcarbamoyl chloride with a substituted phenol of formula (IV) to form an aryl dimethylcarbamate of formula (III)

Formula (III) Formula (IV) where Rj is an electron withdrawing group; R₂ and R₃ are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or R₂ and R3 when placed ortho to each other form benzene ring; R3 and R4 are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R3 and R4 together with nitrogen form 3 to 7 members heterocyclic ring; ii. optionally isolating the aryl dimethylcarbamate of formula (III) obtained in the step '; and iii. reacting the aryl dimethylcarbamate of formula (III) obtained in the step with 3- dimethylaminophenol.

The process of the present invention is advantageously carried out in one-pot i.e. without isolating aryl dimethylcarbamate of formula (III). In a preferred embodiment R_\ is an electron withdrawing group selected from N0₂, CN or CO-alkyl; and R₂ is hydrogen or electron withdrawing group selected from N0₂, CN or CO-alkyl; and R₃ is hydrogen.

The steps 'i' and 'iii' are preferably carried out in presence of a base and a suitable solvent.

The base which may be used in the step (i) of present invention is organic or inorganic. The base used for the step (iii) is inorganic. Examples of organic base include tertiary amines such as trialkyl amine. Examples of inorganic base include alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide and mixture thereof. Examples of alkali metal carbonate include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate. Examples of alkaline earth metal carbonate include calcium carbonate and magnesium carbonate. Examples of alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate. The examples of alkali metal hydroxide include potassium hydroxide and sodium hydroxide. The preferred base for the step (i) is triethylamine. The preferred base for the step (iii) is potassium hydroxide.

The base is conveniently used in an amount, relative to dimethylcarbamoyl chloride, preferably in a range between 1 to 2 equivalents, more preferably 1.2 to 1.8 equivalents. The most preferred quantity of the base is 1.4 to 1.6 equivalents.

The suitable solvent used according to the process of the invention in both the process steps may be selected from any polar solvent, non polar solvent or mixture thereof. The preferred solvent is toluene. The process of the present invention may be carried out at suitable temperature. To minimize the decomposition of products and impurity formation the reaction is carried out at 60°C to 200°C, more preferably at 80°C to 150°C. The most preferred reaction temperature is 100°C to 125°C.

The resulting 3-dimethylaminophenyl dimethylcarbamate is isolated as a pale yellow oil in 75 - 96% yield with HPLC purity greater than 98%, hence the process avoids the step of distillation which was essentially required for purification in the prior art processes.

The pure 3-dimethylaminophenyl dimethylcarbamate obtained by the process of present invention can be quaternisd with dimethylsulphate using known procedure to afford neostigmine methylsulphate in 81 to 92% yield with 98.8 to 99.7% HPLC purity.

The pure neostigmine methylsulphate obtained by the process of the invention may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques. Further the dosage form may be immediate release or extended release.

Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

EXAMPLES:

Example 1

One-pot preparation of 3-dimethylaminophenyl dimethylcarbamate from bis(4- nitrophenyl)carbonate

Step (i)

A 250 ml round bottom flask was charged with bis(4-nitrophenyl)carbonate (20.5 gm) and toluene (100 ml); and the flask was cooled to 0°C to 5°C. Dimethylamine (9.22 gm, 40% aq. solution) was diluted with 10 ml water and added drop wise to the flask at 0°C to 5°C. After completion of addition the flask was kept at room temperature for stirring for 3 hours. The reaction mixture was washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The filtrate was used in the next step.

Step (ii)

A 250 ml round bottom flask was charged with 3-dimethylaminophenol (11 gm), potassium hydroxide (4.8 gm) and toluene (120 ml); and the reaction mixture was refluxed at 100°C to 1 10°C for 2 hours. The flask was cooled to room temperature and charged with the filtrate from the step (i). The reaction mixture was refluxed at 100°C to 1 10°C for 1.5 hours and filtered. The filtrate was cooled to room temperature and washed with IN sodium hydroxide solution followed by conventional work-up to afford 3- dimethylaminophenyl dimethylcarbamate.

Yield - 12.2 gm (89.70%)

Nature - pale yellow oil

HPLC Purity - 98.42%

Example 2

Preparation of 3-dimethylaminophenyl dimethylcarbamate from bis(4- nitrophenyl)carbonate

Step (i) Preparation of 4-nitrophenyl dimethylcarbamate

The filtrate obtained in the step (i) of the example 1 was concentrated to dryness and recrystallised from toluene to obtain 4-nitrophenyl dimethylcarbamate.

Yield - 13 gm (91.81%)

Nature - light yellow crystalline powder

HPLC Purity - 96.5%

Step (ii) 3-dimethylaminophenyl dimethylcarbamate

A 250 ml round bottom flask was charged with potassium hydroxide (2.24 gm), 3- dimethylaminophenol (5 gm) and toluene (50 ml). The reaction mixture was refluxed at 100°C to 110°C for 2 hours and cooled to room temperature. 4-nitrophenyl dimethylcarbamate (6.5 gm) was added to the flask and refluxed at 100°C to 110°C for 2.5 hours. The reaction mixture was washed IN sodium hydroxide solution, followed by conventional work-up to afford 3-dimethylaminophenyl dimethylcarbamate.

Yield - 5.98 gm (93%)

Nature - pale yellow oil

HPLC Purity - 98.99%

Example 3

One-pot preparation of 3-dimethylaminophenyl dimethylcarbamate from bis(2- nitrophenyl)carbonate

The process is carried out similarly as example 1 using bis(2-nitrophenyl)carbonate instead of bis(4-nitrophenyl)carbonate.

Yield - 88%

Nature - pale yellow oil

HPLC Purity - 98.90%

Example 4

Preparation of 3-dimethylaminophenyl dimethylcarbamate from bis(2- nitropheny l)carbonate .

Step (i) Preparation of 2-nitrophenyl dimethylcarbamate

The process is carried out similarly as example 2 using bis(2-nitrophenyl)carbonate instead of bis(4-nitrophenyl)carbonate to provide 2-nitrophenyl dimethylcarbamate.

Yield 88%

Nature pale yellow

HPLC Purity - 98.90%

Step (ii) Preparation of 3-dimethylaminophenyl dimethylcarbamate The process is carried out similarly as example 2 using 2-nitrophenyl dimethylcarbamate instead of 2-nitrophenyl dimethylcarbamate.

Yield - 96%

Nature - pale yellow oil

HPLC Purity - 98.10%

Example 5

One-pot preparation of 3-dimethylaminophenyl dimethylcarbamate from 4-nitrophenol Step (i)

A 1000 ml four neck round bottom flask with water condenser was charged with 4- nitrophenol (40 gm) and toluene (300 ml); and heated to reflux. Cool the reaction mixture to room temperature. Triethylamine (44.34 gm) was added to the flask, stirred the reaction mixture for 0.5 hour at room temperature. Dimethylcarbamoyl chloride (29.12 ml) was added drop wise to the flask within 10 to 15 minutes, the reaction mixture was heated to reflux and maintained for 3 hours. The reaction mixture was quenched into distilled water, toluene layer was separated.

Step (ii)

A 1000 ml four neck round bottom flask was charged with 3-dimethylaminophenol (40 gm), potassium hydroxide (18.7 gm) and toluene (200 ml). The flask was heated to reflux for one hour, cooled to 90°C and charged with the toluene layer obtained in the step (i). The reaction mixture was heated to reflux and maintained for 3 hours. The reaction mixture was filtered, residue was washed with toluene, followed by conventional work-up to afford 3-dimethylaminophenyl dimethylcarbamate.

Yield - 50 gm (83.70%)

Nature - pale yellow oil

HPLC Purity - 99.4%

Example 6

Preparation of 3-dimethylaminophenyl dimethylcarbamate from 4-nitrophenol Step (i) Preparation of 4-nitrophenyl dimethylcarbamate

The toluene layer which was obtained as per the step (i) of the example 5 was washed with distilled water (500 ml). The organic layer was dried over sodium sulphate and concentrated to dryness. The residue obtained was triturated with hexane and collected by filtration to afford 4-nitrophenyl dimethylcarbamate.

Yield - 55 gm

Nature - light yellow crystalline powder

HPLC Purity - 99.8%

Step (ii) Preparation of 3-dimethylaminophenyl dimethylcarbamate

A 1000 ml four neck round bottom flask was charged with 3-dimethylaminophenol (60 gm), potassium hydroxide (28.05 gm) and toluene (300 ml). The flask was heated to reflux for one hour and cooled to 90°C. The flask was charged with 4-nitrophenyl dimethylcarbamate (54 gm), heated to reflux and maintained for 3 hours. The reaction mixture was filtered and residue was washed with toluene. The toluene layer was washed with 0.5 N sodium hydroxide solution; followed by conventional work-up to afford 3- dimethylaminophenyl dimethylcarbamate.

Yield - 51.5 gm (96.20%)

Nature - pale yellow oil

HPLC Purity - 99.50%

Example 7

One-pot preparation of 3-dimethylaminophenyl dimethylcarbamate from 2-nitrophenol

The process is carried out similar to the example 5 using 2-nitrophenol instead of 4- nitrophenol.

The product was isolated as pale yellow oil (75% yield) and 97.94% HPLC purity.

Yield - 75%

Nature - pale yellow oil

HPLC Purity - 97.94% Example 8

Preparation of 3-dimethylaminophenyl dimethylcarbamate from 2-nitrophenol

Step (i) Preparation of 2-nitrophenyl dimethylcarbamate

The process is carried out similarly as step (i) of example 6, using 2-nitrophenol instead of 4-nitrophenol to afford 2-nitrophenyl dimethylcarbamate.

Yield - 88%

Nature - light yellow crystalline powder

HPLC Purity - 97.94%

Step (ii) Preparation of 3-dimethylaminophenyl dimethylcarbamate

The process is carried out similar to the step (ii) of example 6, using 2-nitrophenyl dimethylcarbamate instead of 4-nitrophenyl dimethylcarbamate.

Yield - 90%

Nature - pale yellow oil

HPLC Purity - 99.06% Example 9

Preparation of neostigmine methylsulphate (General procedure)

A 250 ml four neck round bottom flask was charged with 3-dimethylaminophenyl dimethylcarbamate obtained in the example 1, and acetone. Dimethyl sulphate (1.66 eq) was added drop wise to the flask at room temperature. The reaction mixture was stirred overnight, cooled to 5°C to 10°C for 2 hours, filtered and the filtrate was washed with isopropanol. The residue was dried under vacuum at room temperature to get crude neostigmine methylsulphate, which was purified by recrystallisation from isopropanol.

Yield - 85%

Nature - pale yellow oil

HPLC Purity - 99.21%

Similarly 3-dimethylaminophenyl dimethylcarbamate obtained in the examples 2 to 8 were quaternised to afford neostigmine methylsulphate in 81 to 92 % yield and 98.8 to 99.7 % HPLC purity.

Claims

We claim,

1. Process for preparing 3-dimethylaminophenyl dimethylcarbamate of formula (I)

H

Formula (I) comprising,

a. reacting diaryl carbonate of formula (II) with dimethylamine to form an aryl dimethylcarbamate of formula (III)

Formula (II) Formula (III) where Ri is an electron withdrawing group; R₂ and R₃ are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR₃R₄, mercapto, thioalkyl containing 1 to 7 carbon atoms, or R₂ and R₃ when placed ortho to each other form benzene ring; R₃ and R₄ are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R₃ and R₄ together with nitrogen form 3 to 7 members heterocyclic ring; b. optionally isolating the aryl dimethylcarbamate of formula (III) obtained in the step 'a'; and c. reacting the aryl dimethylcarbamate of formula (III) obtained in step 'a' with 3- dimethylaminophenol.

2. The process as claimed in claim 1, wherein the process is carried out without isolating the aryl dimethylcarbamate of formula (III).

3. The process as claimed in claim 1, wherein Ri is selected from N0₂, CN or CO-alkyl and R₂ is hydrogen or electron withdrawing group selected from N0₂, CN or CO-alkyl.

4. The process as claimed in claims land 3, wherein R) is N0₂; R₂ is N0₂ or hydrogen; and R₃ is hydrogen.

5. The process as claimed in claim 1, wherein the step 'a' is carried out in presence of a solvent.

6. The process as claimed in claim 1, wherein the step 'c' is carried out in presence of a base and a solvent.

7. The process as claimed in claim 6, wherein the base for the step 'c' is selected form atleast one inorganic base.

8. The process as claimed in claim 7, wherein the base is potassium hydroxide.

9. The process as claimed in claims 5 and 6 wherein the solvent is selected from polar solvent, non polar solvent or mixture thereof.

10. The process as claimed in claim 9 wherein the solvent is toluene.

11. Process for preparing 3-dimethylaminophenyl dimethylcarbamate of formula (I)

Formula (I)

comprising,

i. reacting dimethylcarbamoyl chloride with a phenolic compound of formula (IV) to form an aryl dimethylcarbamate of formula (III).

Formula (III) Formula (IV) where Rj is an electron withdrawing group; R₂ and R₃ are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR₃R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or R₂ and R₃ when placed ortho to each other form benzene ring; R₃ and > are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R₃ and R4 together with nitrogen form 3 to 7 members heterocyclic ring;

11. optionally isolating the aryl dimethylcarbamate of formula (III) obtained in step a; and iii. reacting the aryl dimethylcarbamate of formula (III) obtained in step 'a' with 3- dimethylaminophenol.

12. The process as claimed in claim 11, wherein the process is carried out without isolating aryl dimethylcarbamate of formula (III).

13. The process as claimed in claim 11, wherein Ri is selected from N0₂, CN or CO-alkyl and R₂ is hydrogen or electron withdrawing group selected from N0₂, CN or CO-alkyl.

14. The process as claimed in claims 11 and 13, wherein R is N0₂; R₂ is N0₂ or hydrogen; and R₃ is hydrogen.

15. The process as claimed in claim 1 1, wherein the steps 'i' and ii' are carried out in presence of a base and a solvent.

16. The process as claimed in claims 11 and 15, wherein the base for the step 'i' is selected from organic base, inorganic base or mixture thereof.

17. The process as claimed in claim 16, wherein the base for the step 'i' is triethylamine.

18. The process as claimed in claims 11 and 15, wherein the base for the step 'iii' is selected from atleast one inorganic base.

19. The process as claimed in claim 18, wherein the base for the step Mii' is potassium hydroxide.

20. The process as claimed in claims 11 and 15, wherein the solvent is selected from polar solvent, non polar solvent or mixture thereof.

21. The process as claimed in claim 20, wherein the solvent is toluene.