Field of the Invention:
The present invention relates to the field of chemical science and specifically provides an improved and green process for the synthesis of Ranolazine. It also relates to a process for the preparation of intermediates such as 2-chloro-N-(2 6-dimethylphenyl)acetamide and N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide.
Background of the Invention:
Ranolazine  chemically known as N-(2 6-dimethylphenyl)-2-(4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)piperazin-1-yl)acetamide  of the general formula 1  has been approved by US FDA for the treatment of chronic angina pectoris in combination with amlodipine  ß-blockers or nitrates in patients who do not show adequate response to other anti-anginals and is also used for the treatment of epilepsy and other central nervous disorders.

Due to distinguished biological and physicochemical properties of Ranolazine  there has been incredible interest to devise a greener and efficient method for the synthesis of Ranolazine (Formula 1).

US 4 567 264 discloses two processes for the synthesis of Ranolazine. The discrepancy between the two processes is the introduction of substituent groups on nitrogen atom of piperazine ring in different sequence. One of the two procedures include the reaction of 2 6-dimethylaniline with chloroacetyl chloride in the presence of triethylamine and using dichloromethane as solvent followed by reacting with piperazine to get N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide  which is subsequently treated with 2-((2-methoxyphenoxy)methyl)oxirane to get Ranolazine. The starting material 2-((2-methoxyphenoxy)methyl)oxirane is synthesized by carrying a reaction of 2-methoxy phenol with epichlorohydrin in the presence of strong base and a mixture of two solvents vis-à-vis water and dioxane.

Drawbacks of US4 567 264:
(i) Use of triethylamine as base for the amide bond formation  which is harmful  carcinogenic  and corrosive and may cause injure to liver and mucous membranes and use of toxic volatile organic solvents (DCM  dioxane etc.)
(ii) Use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products such as IIb  IIc  IId. In the above patent the yield of 2-((2-methoxyphenoxy)methyl)oxirane has not been mentioned. However in US patent no. US 2011/0151258 A1  the inventors reiterated their experimental condition by reaction of 2-methoxyphenol with epichlorohydrin in the presence of sodium hydroxide in water and dioxane. They have observed the formation of large number of impurities including 43.37% of 1 3-bis(2-methoxyphenoxy)propan-2-ol (IIb) and 0.78% of chloro impurity (IIc) and 2.74% of dihydroxy compounds (IId). Removal of these impurities is very difficult and requires time consuming purification steps  which make the process expensive and incompatible for commercial point of view.
Possible products during the reaction of 2-methoxyphenol (Formula 9) with epichlorohydrin (Formula 7):

II

WO 2008/047388 A2 discloses a reaction of 2 6-dimethylaniline with chloroacetyl chloride in the presence of sodium bicarbonate in water at 0 to 5°C for 3 hrs  followed by treating with piperazine in ethanol under reflux condition for 3 hrs to acquire N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide and the resulting piperazine derivative treated with an 2-((2-methoxyphenoxy)methyl)oxirane in toluene at 120°C for 5 hrs to get
the final product i.e. Ranolazine. The 2-((2-methoxyphenoxy)methyl)oxirane is prepared by carrying the reaction of 2-methoxyphenol with epichlorohydrin in the presence of sodium hydroxide and tetrabutylammonium bromide in toluene at room temperature (RT)  i.e. 37°C for 5 hrs. They have observed the formation of 84.21% of 2-((2-methoxyphenoxy)methyl)oxirane and 7.59% of dimer impurity (IIb).
Drawbacks of WO 2008/047388 A2:
(i) Use of base and carrying the reaction at 0 to 5°C during the amide bond formation and use of volatile organic solvents (Toluene  EtOH etc.)
(iii) Use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  attained by carrying the reaction of 2-methoxyphenol with epichlorohydrin. They have observed the formation 7.59% of dimer impurity (IIb). This process does not stop or completely minimize the formation of dimer impurity (IIb) during the reaction of 2-methoxyphenol with epichlorohydrin. Removal of these impurities is very difficult and requires time consuming purification steps  which make the process expensive and incompatible for commercial point of view.

US 2011/0151258 A1 discloses the reaction of 2 6-dimethylaniline with chloroacetyl chloride in the presence of sodium carbonate in dichloromethane at 10 to 25°C for 2.5 hrs  which is reacted with piperazine in methanol under reflux condition for 3 hrs to acquire N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide and the resulting piperazine derivative is treated with an 2-((2-methoxyphenoxy)methyl)oxirane in presence of acetone under reflux condition for 15-16 hrs to get the final product i.e. Ranolazine. The 2-((2-methoxyphenoxy)methyl)oxirane is prepared by carrying the reaction of 2-methoxyphenol with epichlorohydrin in the presence of sodium hydroxide in water at RT for 18 hrs. They have observed the formation of 98.28% of 2-((2-methoxyphenoxy)methyl)oxirane (IIa) and 0.29% of dimer impurity (IIb) and 0.15% of chloro impurity (IIc) and 0.70% of dihydroxy impurity (IId).
Drawbacks of US 2011/0151258 A1:
1. Use of base and carrying the reaction at lower temperature (10°C) during amide bond formation and use of volatile organic solvents (DCM  MeOH  Acetone)
2. Carrying the reaction under nitrogen atmosphere and reflux condition.

3. Use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  attained by carrying the reaction of 2-methoxyphenol with epichlorohydrin. This process does not stop or completely minimize the formation of impurities such as IIb  IIc  IId.
4. Since it requires 4 steps  which involves 1 extra purification step and wasting of solvents and time consuming process.
5. involving the synthesis of 2-((2-methoxyphenoxy)methyl)oxirane by carrying the reaction of 2-methoxy phenol with epichlorohydrin  which leads to formation of large number of byproducts such as 1 3-bis(2-methoxyphenoxy)propan-2-ol (IIb) and chloro impurity (IIc) and dihydroxy compounds (IId). Removal of these impurities is very difficult remove and makes the process expensive.
6. It describes two processes for the synthesis of ranolazine  both processes involves 4 steps. It covered/performed all reactions in water and other organic solvents. The overall yield in case of method A was 80% and Method B was 85 %

Method A:
The first process involves carrying the reaction of 2 6-dimethylaniline with chloroacetyl chloride and which is reacted with piperazine and the resulting piperazine derivative treated with an 2-((2-methoxyphenoxy)methyl)oxirane to get the final product i.e. ranolazine. The 2-((2-methoxyphenoxy)methyl)oxirane synthesized by reaction 2-methoxy phenol with epichlorohydrin.

Method B:
The second process involves carrying the reaction of ring opening of 2-((2-methoxyphenoxy)methyl)oxirane with piperazine and the resulting piperazine derivative treated with 2-chloro-N-(2 6-dimethylphenyl)acetamide to get ranolazine. The starting material 2-((2-methoxyphenoxy)methyl)oxirane synthesized by reaction 2-methoxy phenol with epichlorohydrin.

Keeping in view of formation of by products during synthesis of 2-((2-methoxyphenoxy)methyl)oxirane by the reaction of 2-methoxy phenol with epichlorohydrin  herein a new route was designed for the synthesis of ranolazine by avoiding the involvement of above mentioned starting material i.e. 2-((2-methoxyphenoxy)methyl)oxirane.

WO 2010/097805 A1 discloses the reaction of 2 6-dimethylaniline with chloroacetyl chloride in the presence of K2CO3 in water and acetone at 5 to 15°C for 5 hrs  which is reacted with piperazine in isopropyl alcohol under reflux condition for 60 min to acquire N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide and the resulting piperazine derivative treated with an 2-((2-methoxyphenoxy)methyl)oxirane in the presence of toluene and methanol at 60°C to get the final product i.e. Ranolazine.
Drawbacks of WO 2010/097805 A1:
(i) Use of base and carrying the reaction at lower temperature (5°C) during amide bond formation and use of volatile organic solvents (Acetone  Toluene  MeOH  Acetone)
(ii) Carrying the reaction under nitrogen atmosphere and reflux condition.
(iii) Use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  attained by carrying the reaction of 2-methoxyphenol with epichlorohydrin. This process does not stop or completely minimize the formation of impurities such as IIb  IIc  IId.
In the prior art  all reported procedures for the synthesis of Ranolazine use the 2-((2-methoxyphenoxy)methyl)oxirane as starting material  several efforts has been made by many investigators to reduce formation of by-products (IIb  IIc  IId.) during the reaction of 2-methoxyphenol with epichlorohydrin. However  many of these reported procedures often require volatile organic solvents to carry out the reactions and harsh reaction conditions and suffer with formation of by-products (IIb  IIc  IId.) during the reaction of 2-methoxyphenol with epichlorohydrin.

Comparison of prior art (Vs.) New invention for the synthesis of Ranolazine

Entry Number of steps of Prior invention
(Vs.)
New invention Solvents of Prior invention
(Vs.)
New invention Catalyst
or
Reagents of Prior invention
(Vs.)
New invention Time (h) of
of Prior invention
(Vs.)
New invention Drawbacks prior invention
(Vs.)
Advantages of New invention Reference
1 4
(Vs.)
3 Dichloromethane
Ethanol
1 4-Dioxane
Water
(Vs.)
Water
Triethylamine
(Vs.)

SDS
TBAI
K2CO3
14
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult and it requires time consuming purification steps  which make the process expensive and incompatible for commercial point of view.
(ii) Use of triethylamine as base during the amide bond formation  which is harmful  carcinogenic (iii) Use of toxic volatile organic solvents (dichloromethane  1 4-dioxane etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. US 4 567 264
2 4
(Vs.)
3 Toluene
Tetrahydrofuran
Ethanol
(Vs.)
Water TBAB
NaOH
Na2CO3
(Vs.)

SDS
TBAI
K2CO3
18
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of volatile organic solvents (Tetrahydrofuran  Toluene etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. PCT Int. Appl. 2008/047388 A2
3 4
(Vs.)
3
Water
DCM
MeOH
(Vs.)
Water

NaOH
TBAB
(Vs.)

SDS
TBAI
K2CO3
29
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of volatile organic solvents (Dichloromethane and Methanol etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. PCT Int. Appl. 2010/023687 A2
4 4
(Vs.)
3 Water
Acetone
Isopropanol
MeOH
Toluene
(Vs.)
Water

K2CO3
(Vs.)

SDS
TBAI
K2CO3
18
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of volatile organic solvents (Isopropanol  Methanol  Toluene etc.
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. PCT Int. Appl. 2010/097805 A1
5 4
(Vs.)
3 Water
Dioxane
DCM
EtOH
MeOH
Toluene
(Vs.)
Water

Triethylamine
NaOH
(Vs.)

SDS
TBAI
K2CO3

14
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of volatile organic solvents (Dichloromethane and Methanol etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. EP 0126449 A1
6 4
(Vs.)
3 Dichloromethane
Methanol
Acetone
Water
(Vs.)
Water
Na2CO3
NaOH
(Vs.)

SDS
TBAI
K2CO3
32
(Vs.)
9 i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) Use of triethylamine  which is harmful  carcinogenic  and corrosive.
(iii) It involves the use of volatile organic solvents (Dichloromethane and Methanol etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. US 2011/0151258 A1
7 4
(Vs.)
3 Dichloromethane
1 4-Dioxane
(Vs.)
Water

Triethylamine
(Vs.)
SDS
TBAI
K2CO3
30
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of triethylamine  which is harmful  carcinogenic
(iii) It involves the use of volatile organic solvents (Dichloromethane and 1 4-Dioxane etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. US 4 567 264
8 4
(Vs.)
3 Toluene
Tetrahydrofuran
Ethanol
(Vs.)
Water

TBAB
NaOH
Na2CO3
(Vs.)

SDS
TBAI
K2CO3
20
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) It involves the use of volatile organic solvents (Tetrahydrofuran  Toluene etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. PCT Int. Appl. 2006/008753 A1
9 4
(Vs.)
3 Water
1 4-Dioxane
Dichloromethane
Dimethylformamide
(Vs.)
Water
Triethylamine
NaOH
(Vs.)

SDS
TBAI
K2CO3
65
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) Use of triethylamine  which is harmful  carcinogenic  and corrosive
(iii) It involves the use of volatile organic solvents (Dichloromethane  1 4-Dioxane  Dimethylformamide etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. EP 0126449 A1
10 4
(Vs.)
3 Water
Dichloromethane
Methanol
Acetone
(Vs.)
Water
NaOH
Na2CO3
(Vs.)

SDS
TBAI
K2CO3
20
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult and it requires time consuming purification steps  which make the process expensive and incompatible for commercial point of view
(ii) It involves the use of volatile organic solvents (Dichloromethane  Methanol etc.)
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. US 2011/0151258 A1
11 7
(Vs.)
3 Tetrahydrofuran
DCM Benzene
Toluene
Et2O
(Vs.)
Water

Tetrabutylammoniumhydrogensulfate
CuCl2
Pyridine
Triethylamine
KI

(Vs.)

SDS
TBAI
K2CO3
40
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products.
(ii) Use of triethylamine  which is harmful  carcinogenic  and corrosive
(iii) It involves the use of volatile organic solvents (Dichloromethane  Benzene etc.)
(iii) It involves large number of steps
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. Biocatal. Biotranfor. 2005  23  45
12 5
(Vs.)
3 Water
Acetone
Chloroform
Ethanol
(Vs.)
Water

Triethylamine
NaI
CaCl2
HCl
(Vs.)

SDS
TBAI
K2CO3
75
(Vs.)
9 (i) It involves the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  which is obtained by carrying the reaction of 2-methoxyphenol with epichlorohydrin  and associates with by-products. Removal of these impurities is difficult
(ii) Use of triethylamine  which is harmful  carcinogenic  and corrosive
(iii) It involves the use of volatile organic solvents (Chloroform  Acetone etc.)
(ii) It involves large number of steps
(Vs.)
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine
(ii) Lesser number of steps
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products. Biocatal. Biotranfor. 2005  23  45

Owing to its potential adverse impact and increasing safety concern of chemical processes on global ecology the environment protection agency has urged to frame tight legislation to maintain greenness in synthetic pathways and processes. In the context of sustainable chemistry development  organic reactions in aqueous medium have gained momentum. Consequently  application of water as reaction media has become quite trendy nowadays. There has been tremendous interest to devise a greener and efficient greener process for the synthesis of Ranolazine.
Objects of the Invention:
The main object of the present invention is to provide a concise and efficient protocol for the total synthesis of Ranolazine of the general formula 1 in an aquatic condition. Another object of the present invention is to provide an efficient process for the synthesis of intermediates such as 2-chloro-N-(2 6-dimethylphenyl)acetamide of the general formula 4 and N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide of the general formula 6.
Summary of the Invention:
The present invention provides a concise and efficient process for the total synthesis of N-(2 6-dimethylphenyl)-2-(4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)piperazin-1-yl)acetamide of the general formula 1  also known as Ranolazine. It mainly focuses on the use of water as reaction media throughout the process for the synthesis of Ranolazine.

Detailed Description of the Invention:
Accordingly  the present invention describes a concise and efficient aqueous mediated process for the total synthesis of Ranolazine  which may be represented by the formula 1.

The key aspect of the present invention is to focus on green chemistry to carry out the reactions by using water as solvent throughout the process and minimizing the number of steps as well as the formation of side products.
The compound of formula 1 can be synthesized by ring opening of epichlorohydrin (Formula 7) with N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) followed by O-alkylation of 2-methoxyphenol (Formula 8). The compound of formula 6 can be obtained by N-monoalkylation of piperazine (Formula 5) with 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4). The intermediate compound of formula 4 can be obtained by acylation of 2 6-dimethylaniline (Formula 2) with chloroacetic anhydride (Formula 3).

Accordingly  the main object of the invention is to provide an improved  rapid and greener process for the total synthesis of Ranolazine of the general formula 1 

comprising the steps of:
Step 1) reacting 2 6-dimethylaniline (Formula 3) with chloroacetic anhydride (Formula 2) in suitable solvent  or a solvent surfactant mixture as described herewith  to afford 2-chloro-N-(2 6-dimethylphenyl)acetamide of the general formula 4 

Step 2) reacting 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) with piperazine (Formula 5) in presence of phase transfer catalyst in suitable solvent to afford N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide of the general formula 6 

Step 3) reacting N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) with epichlorohydrin (Formula 7) followed by 2-methoxyphenol (Formula 8) in presence of a base as described herewith in suitable solvent to afford Ranolazine (Formula 1).

Another embodiment of this invention is the synthesis of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) by
a) reacting 2-chloroacetic anhydride (Formula 2) with 2 6-dimethyl aniline (Formula 3) in solvent system includes organic solvents (hydro carbons  protic
polar  aprotic polar includes flourous alcohols) and water  and preferably water is used or
b) reacting 2-chloroacetyl chloride with 2 6-dimethyl aniline (Formula 3) in presence of surfactant comprising anionic and cationic and neutral surfactant and solvent system comprising of organic solvents (hydro carbons  protic polar  aprotic polar includes flourous alcohols) and water  and preferably water is used.
Yet another embodiment of this invention is to isolate formula 4 by 
a. filtering the reaction mixture;
b. Collecting the precipitate;
c. washing the precipitate of step b) with cold water; and
d. drying the precipitate of step c) to get white solid.
Still another embodiment of this invention is the synthesis of N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) of step 2) has been carried out by reacting 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) with piperazine (Formula 5) in solvent system includes organic solvents (hydro carbons  protic polar  aprotic polar includes flourous alcohols) and water. Among these solvents  water is the most preferred solvent.
Further embodiment of this invention is the synthesis N-(2  6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) by reacting 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) with piperazine (Formula 5) in the catalytic system includes anion surfactant  cationic surfactant  neutral surfactant and phase transfer catalysts.
In yet another embodiment of this invention is the use of tetrabutylammonium iodide as catalyst.
Another embodiment of this invention is the use of piperazine (Formula 5) in 1.1 to 2 equivalents with respect to 2-chloro-N-(2  6-dimethylphenyl)acetamide (Formula 4)  Predominantly preferred amount is 1.5 equivalents.
Still another embodiment of this invention is the reaction of step 2) is carried out at a temperature of 60 to 80°C  preferably at 60°C.

Further embodiment of this invention is the solvent system in step 3) for the synthesis of Ranolazine (Formula 1)  includes organic solvents (hydro carbons  polar aprotic  aprotic and alcohols includes florous alcohols) and water 
Another embodiment of this invention is the base used in step 3) for the synthesis of Ranolazine (Formula 1)  is selected from a group comprising of sodium hydroxide  potassium hydroxide  calcium hydroxide  sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate and the like  preferably potassium carbonate is used.
Yet another embodiment of this invention is the use of K2CO3 in step 3) for the synthesis of Ranolazine (Formula 1)  in 1.0 to 2 equivalents with respect to 2-methoxyphenol (Formula 8) and the preferred amount is 1.3 equivalents.
Still another embodiment of this invention is the reaction of step 3) is carried out initially at RT for 60 min and later at 60 to 100°C  preferably at 80°C.
Examples:
The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations. All embodiments apparent to a process there in the art are deemed to fall within the scope of the present invention.
Example 1

Step 1: Synthesis of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4)

To a magnetically stirred solution of 2 6-dimethylaniline (Formula 3) (20 mmol) in 30 mL water  2-chloroacetic anhydride (Formula 2) (20 mmol  1 equiv) is added at RT. After completion of reaction (2 hrs  monitored by TLC)  the precipitate is filtered off and washed
with cold water and dried to get pure 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) (table 1  94%).
Example 2
Synthesis of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4)
To a magnetically stirred solution of 2 6-dimethylaniline (20 mmol) in 20 mL trifluoroethanol  2-chloroacetic anhydride (20 mmol  1 equiv) is added at RT. After completion of reaction (30 min  monitored by TLC)  the reaction mixture is concentrated under rotary vacuum evaporator and crude solid is washed with water to get pure 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) (table 1  94%).

Table 1: Influence of solvent on N-acylation of 2 6-dimethylaniline with chloroacetic anhydridea
Entry Solvent (1 mL) Yield (%)b
1 Water 94
2 MeOH 21
3 EtOH 20
4 iPrOH 17
5 tBuOH 15
6 1 4-Dioxane trace
7 THF trace
8 CH3CN trace
9 DMF trace
10 Toluene trace
11 MeNO2 trace
12 TFE 94c
13 HFIP 94c
14 None trace
aReaction of 2 6-dimethyl aniline (1 mmol  1 equiv) with chloroacetic anhydride (1 mmol  1 equiv) in different solvents (1 mL) at RT for 2 hrs. bIsolated yield. cReaction completed in 30 min.
Example 3
Synthesis of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4)
To a magnetically stirred solution of 2 6-dimethylaniline (20 mmol) in Water (100 mmol)  2-chloroacetyl chloride (26 mmol  1.3 equiv) is added at 15-20°C. After completion of reaction (30 min  monitored by TLC)  the reaction mixture is filtered and washed with water to get pure 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) (table 2  90%).

Table 2: Effect of surfactant on acetylation of 2 6-dimethylaniline with chloroacetyl chloridea
Entry Surfactant (10 mol%) Yield 4 (%)b
1 None 35c
2 None 25
3 Span 80 65
4 Tween 80 68
5 Triton X-100 71
6 ß-Cyclodextrin hydrate 62
7 Benzalkonium Chloride 52
8 Tetrabutylammonium bromide 45
9 Tetrabutylammonium iodide 48
10 Cetyltrimethylammonium bromide 55
11 Hexadecyl Pyridinium Chloride 52
12 SDS 80
13 SDS 90c
14 Sodium Deoxy Cholate 65
15 Sodium Dioctyl Sulfosuccinate 78
aReaction of 2 6-dimethylaniline (1 mmol  1 equiv) with chloroacetyl chloride (1.2 mmol  1.2 equiv)  in presence of surfactant (10 mol% )  in water (50 mmol) at 20°C for 30 min. bIsolated yield
cReaction is carried out using 5 mmol amount of water
The surfactant used in the reaction of 2 6-dimethylaniline with chloroacetyl chloride is standardized using different surfactants  as summarized in Table 2 above. A very high yield of 90% is obtained in presence of SDS  in 5 mmol of water at 20°C for 30 min.
Example 4
Step 2: Synthesis of N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6)
To a magnetically stirred solution of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) (15 mmol) and tetrabutylammonium iodide (10 mol%) in 15 mL water  piperazine (Formula 5) (22.5 mmol  1.5 equiv) is added at RT. The reaction mixture is heated to 60°C and allowed to stir for 3 hrs. After completion of reaction  the reaction mixture is cooled to 5-10°C  sodium bicarbonate and methanol are added and the reaction mixture is stirred for 60 min. The reaction mixture is then filtered to remove trace amount of dimer and the filterate is extracted with dichloromethane and concentrated under rotary vacuum evaporator. The white precipitate thus obtained is washed with cold water to get N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) (table 3  90% yield).

Further  influence of surfactant/ phase transfer catalyst is studied on reactivity and selectivity of reaction of 2-choloro-N-(2 6-dimethylphenyl)acetamide with piperazine. The results thus obtained are as given in Table 3.

Table 3: Influence of surfactant/phase transfer catalyst on reactivity and selectivity of reaction of 2-chloro-N-(2 6-dimethylphenyl)acetamide with piperazinea
Entry Surfactant Yield (%)b
Formula 6 Formula 6a
1 None trace
2 Span 80 10 --
3 Tween 80 14 --
4 Triton X-100 52 13
5 Triton X-114 55 15
6 Triton X-135 50 15
7 ß-Cyclodextrin hydrate 30 8
8 Benzalkonium Chloride 31 10
9 Tetrabutylammonium fluoride 35 10
10 Tetrabutylammonium chloride 48 5
11 Tetrabutylammonium bromide 87 trace
12 Tetrabutylammonium iodide 90 trace
13 Cetyltrimethylammonium bromide 81 trace
14 Hexadecylpyridinium Chloride 40 10
15 SDS 42 13
16 Sodium Deoxycholate 38 12
17 Sodium Dioctyl Sulfosuccinate 59 20
18 Cetrimide 35 15

aReaction of 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) (1 mmol  1 equiv) with piperazine (Formula 5) (1 mmol  1.5 equiv) in presence of catalyst (10 mol% ) in water (1 mL) at 60°C for 3 hrs. bIsolated yield.
Consequently  piperazine amount has been optimized  and it is found that 1.5 equivalents is required for complete conversion.
Subsequently  temperature optimization study has also been performed  it is observed that a temperature of 60°C and time of 3 hrs is required for complete conversion.

Example 5
Third step is the one-pot synthesis of Ranolazine (Formula 1)  for which ring opening of epichlorohydrin (Formula 7) with piperazine derivative (Formula 6) to form 2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-N-(2 6-dimethylphenyl)acetamide (Formula 9) is performed in various solvents and the results thus obtained are shown as under:
Synthesis of 2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-N-(2 6-dimethylphenyl)acetamide (Formula 9)

Table 4: Influence of solvent on ring opening of epichlorohydrin (Formula 7) with piperazine derivative (Formula 6)a

Entry Condition Yield (%)b
1 Water 97
2 MeOH 20
3 EtOH 18
4 iPrOH 19
5 tBuOH 15
6 1 4-Dioxane trace
7 THF trace
8 CH3CN trace
9 DMF trace
10 Toluene trace
11 MeNO2 trace
12 TFE 25
13 HFIP 31

aReaction of epichlorohydrin (Formula 7) with Formula 6 (1 equiv) in different solvents (1 mL) at RT for 60 min. bIsolated yield.

Next step is O-alkylation of halohydrin (Formula 9) with 2-methoxyphenol (Formula 8) in the presence of base in water. It is found that reaction should be carried out at 80°C and 1.3 equivalents of base is optimum for complete conversion (table 5).

Example 6

Synthesis of Ranolazine (Formula 1):

Table 5: Synthesis of Ranolazine (Formula 1)a

Entry Base
(1.3 equiv) Surfactant
(20 mol%) temp (°C) time (h) Yield (%)b
1 None SDOSS RT 10 0
2 None SDOSS reflux 10 0
3 None TBAI reflux 10 0
4 K2CO3 -- RT 10 0
5 K2CO3 -- 60 5 75
6 K2CO3 -- 80 5 93
7 CS2CO3 -- RT 10 --
8 K2CO3 -- 60 5 78
9 CS2CO3 -- 80 5 94
aReaction of o-methoxy phenol (Formula 8) (1 mmol) with halohydrin derivative (Formula 9) (1 mmol)  in presence of base  in water (1 mL).
bIsolated yield.

Once optimized the reaction condition for the synthesis of Ranolazine  it is planned to perform one-pot reaction of ring opening of epichlorohydrin (Formula 7) with piperazine derivative (Formula 6) at RT in water for 1h followed by O-alkylation of 2-methoxy phenol (Formula 8) in presence of K2CO3 at 80°C for 5 hrs.
Example 7
Step 3: Synthesis of Ranolazine (Formula 1)
To a magnetically stirred solution of N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) (10 mmol) in 15 mL water  epichlorohydrin (Formula 7) (10 mmol  1 equiv) is added at RT and allowed to stir for 60 min. After completion of reaction (monitored by TLC)  2-methoxyphenol (Formula 8) (10 mmol) and K2CO3 (13 mmol  1.3 equiv) are added and the reaction is heated to 80°C and allowed to stir for 5 hrs. The reaction mixture is then brought to RT  neutralized with NaHCO3 and cooled to 0-5°C. The temperature is maintained for 30 minutes and the precipitate is filtered and washed with methanol and dried under rotary vacuum evaporator to get pure Ranolazine (Formula 1) (89%).
One-pot synthesis of Ranolazinea b

aReaction of ring opening of epichlorohydrin (Formula 7) with piperazine derivative (Formula 6) in water at RT for 60 min followed by addition of 2-methoxy phenol (Formula 8) at 80°C for 5 hrs. bIsolated yield

This invention:

Advantages of this invention

Preferred Catalyst/
Reagent Advantages
SDS
TBAI
K2CO3
(i) It involves the use of the water promoted/mediated process throughout the synthesis of Ranolazine.
(ii) It involves lesser number of steps ( only 3 steps).
(iii) It avoids the use of 2-((2-methoxyphenoxy)methyl)oxirane as starting material  the synthesis of it always leads to formation of by-products.
(iv) It requires shorter reaction time (only 9 hours).
(v) It leads to Yield augmentation by minimizing the side product formation.
(vi) It involves the use of commercially available starting material and catalyst.
(vii) It involves easy-to-handle starting material and catalyst.

WE CLAIM:

1. An improved  rapid and greener process for the total synthesis of Ranolazine of the general formula 1 

comprising the steps of:
Step 1) reacting 2  6-dimethylaniline (Formula 3) with chloroacetic anhydride (Formula 2) in suitable solvent  or a solvent surfactant mixture as described herewith  to afford 2-chloro-N-(2 6-dimethylphenyl)acetamide of the general formula 4 

Step 2) reacting 2-chloro-N-(2 6-dimethylphenyl)acetamide (Formula 4) with piperazine (Formula 5) in presence of phase transfer catalyst in suitable solvent to afford N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide of the general formula 6 

Step 3) reacting N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) with epichlorohydrin (Formula 7) followed by 2-methoxyphenol (Formula 8) in presence of a base as described herewith in suitable solvent to afford Ranolazine (Formula 1).

2. The process as claimed in claim 1  wherein step 1) synthesis of Formula 4 from Formula 2 and Formula 3 is carried out by
a. a solvent system selected from a group comprising of organic solvents (hydro carbons  protic polar  aprotic polar includes flourous alcohols)  and water  and preferably water is used  or
b. by reacting Formula 3 in presence of a surfactant comprising anionic  cationic and neutral surfactant  and a solvent system comprising of organic solvents (hydro carbons  protic polar  aprotic polar includes flourous alcohols) and water  and preferably water is used.
3. The process as claimed in claim 1  wherein step 1) the Formula 4 is isolated by 
a. filtering the reaction mixture;
b. Collecting the precipitate;
c. washing the precipitate of step b) with cold water; and
d. drying the precipitate of step c) to get white solid.
4. The process as claimed in claim 1  wherein step 2) synthesis of N-(2 6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) is carried out in a solvent system comprising of organic solvents (hydro carbons  protic polar  aprotic polar includes flourous alcohols) and water.
5. The process as claimed in claim 4  wherein step 2) synthesis of N-(2  6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (Formula 6) of step 2) is carried out optionally in the catalytic system consisting essentially of anion surfactant  cationic surfactant  neutral surfactant and phase transfer catalysts.
6. The process as claimed in claim 5  wherein said catalyst is tetrabutylammonium iodide.
7. The process as claimed in claim 1  wherein piperazine (Formula 5) is used in 1.1 to 2 equivalents with to 2-chloro-N-(2  6-dimethylphenyl)acetamide (Formula 4).
8. The process as claimed in claim 7  wherein piperazine (Formula 5) is used in 1. 5 equivalent with to 2-chloro-N-(2  6-dimethylphenyl)acetamide (Formula 4).

9. The process as claimed in claim 1  wherein the reaction of step 2) is carried out at a temperature of 60°C to 80°C.
10. The process as claimed in claim 9  wherein the reaction of step 2) is carried out at a temperature of 60°C.
11. The process as claimed in claim 1  wherein the solvent system in step 3) for the synthesis of Ranolazine (Formula 1)  includes organic solvents (hydro carbons  polar aprotic  aprotic and alcohols includes florous alcohols) and water.
12. The process as claimed in claim 11  wherein the solvent is water.
13. The process as claimed in claim 1  wherein said base used in step 3) is selected from a group comprising of sodium hydroxide  potassium hydroxide  calcium hydroxide  sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate.
14. The process as claimed in claim 13  wherein the base is potassium carbonate.
15. The process as claimed in claim 1  wherein the base is used at 1.0 to 2 equivalents with respect to 2-methoxyphenol (Formula 8).
16. The process as claimed in claim 15  wherein the base is used at 1.3 equivalent with respect to 2-methoxyphenol (Formula 8).
17. The process as claimed in claim 1  wherein the reaction of step 3) is carried out initially at room temperature (RT)  i.e. 37°C for 60 min followed by 60°C to 100°C.
18. The process as claimed in claim 17  wherein the reaction of step 3) is carried out initially at RT for 60 min followed by 80°C.