Description:Field of the invention:
The present invention relates to an improved process for the preparation of Oxetacaine of formula-1.

Formula-1
The present invention also relates to an improved process for the preparation of Oxetacaine intermediate of formula-2

Formula-2
Background of the invention:
Oxetacaine is chemically known as 2,2'-(2-Hydroxyethylimino) bis [N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide].
Oxetacaine is also known as Oxethazaine indicated as gastrointestinal mucosal local anesthetic for the relief of pain associated with peptic ulcer disease or esophagitis.
US2780646 patent discloses the process for the preparation of Oxetacaine by reacting 2-chloro-N-methyl-N-omega-phenyl-tertiary-butylacetamide with ethanol amine in-presence of potassium carbonate in n-butanol.
Process described in US’646 patent is shown in the following scheme

The above said process has some disadvantages i.e., usage of benzene in workup process. Benzene is a carcinogenic solvent. Also the above said reaction requires longer hour reaction time (20 hours) for the completion of reaction.
Moreover there is lack of specific literature for the preparation of Oxetacaine. Thus, there remains a need to develop an improved process for the preparation of Oxetacaine, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any toxic and/or costly solvents or reagents and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Oxetacaine, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a process for the preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methylacetamide of formula-2.
The second embodiment of the present invention provides a process for the preparation of Oxetacaine of formula-1.
The third embodiment of the present invention provides a process for the preparation of crystalline form of Oxetacaine of formula-1.
Brief description of the drawings
Figure 1: Illustrates powder X-ray diffraction (PXRD) pattern of crystalline form of Oxetacaine of formula-1.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether
solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl
sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic
solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term "base" used in the present invention selected from but not limited
to inorganic base selected from "alkali metal carbonates" such as sodium
carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal
bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like;
"alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide,
lithium hydroxide and the like; alkali metal hydrides such as sodium hydride,
potassium hydride, lithium hydride and the like mixtures thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
The term “HPLC” as used in the present invention herein refers to high-performance liquid chromatography.
"Substantially pure" as used in the present invention herein refers to the compound of formula-1 is substantially free from the impurities and having purity ranges from about 99.0% to 99.99% as measured by a liquid chromatography method.
The first embodiment of the present invention provides a process for the
preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methylacetamide of formula-2, comprising: reacting 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide of formula-3 with mono ethanolamine to provide N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methyl acetamide of formula-2

and optionally purifying the compound to provide substantially pure compound.
In first aspect of first embodiment, the above step is optionally carried out in-presence of a base selected from but not limited to alkali metal carbonates or alkali metal bicarbonates, preferably sodium carbonate.
In second aspect of first embodiment, the above step is optionally carried out in a solvent selected from but not limited to alcoholic solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures, preferably n-butanol.
In third aspect of first embodiment, the above step is optionally is optionally carried out in presence of metal iodide and phase transfer catalyst.
Wherein metal iodide selected from but not limited to copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide (NaI), preferably sodium iodide; phase transfer catalyst used is quaternary ammonium salts selected from but not limited to tetramethyl ammonium salt, tetraethyl ammonium salt, benzyl triethyl ammonium salt, benzyl trimethyl ammonium salt, benzyl tributyl ammonium salt, tetrabutyl ammonium salt such as tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI); bromidetetraphenylphosphonium bromide (TPPB) or tetrabutylphosphonium bromide (TBPB), preferably tetrabutyl ammonium bromide (TBAB).
The inventors of present invention have also preformed different experiments by carried out the above reaction with different mole equivalent of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide formula-3 and mono ethanol amine.
After several experiments and significant efforts the inventors of present invention have identified the critical and pivotal mole equivalent ratio range for the above reaction.
In fourth aspect of first embodiment, the amount of mono ethanolamine used in the above reaction is ranges from 8 to 14 mole equivalent with respect to 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide of formula-3 which is crucial for formation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methyl acetamide of formula-2 and impacts the yield, purity and avoids formation of dimer compound of formula-2.
The second embodiment of the present invention provides a process for the
preparation of Oxetacaine of formula-1, comprising: reacting N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methylacetamide of formula-2 with 2-chloro-N-methyl-N-(2-methyl-1-phenyl propan-2-yl) acetamide to provide Oxetacaine of formula-1

and optionally purifying the compound to provide substantially pure compound of Oxetacaine of formula-1.
In first aspect of second embodiment, the above step is optionally carried out in-presence of a base selected from but not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide.
In second aspect of second embodiment, the above step is optionally carried out in a solvent selected from but not limited to hydrocarbon solvent selected from n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene or mixtures thereof, preferably toluene.
The third embodiment of the present invention provides a process for the preparation of crystalline form of Oxetacaine of formula-1, comprising:
a) dissolving Oxetacaine of formula-1 in a solvent,
b) isolating crystalline form of Oxetacaine of formula-1.
Dissolving compound in step-a) can be done by optionally heating the
mixture to a temperature ranging from about 25°C to reflux temperature of the
solvent used.
The solvent used in step-a) selected from alcohol solvents
or ketone solvents or any of the mixtures thereof; “isolating” in step-b) refers to solvent removal by known techniques which are selected from distillation, decanting, filtration, centrifugation, evaporation, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, by combining with an anti-solvent; wherein anti-solvent is different from the solvent used in step-a), or by any other conventional methods known in the art. Dried the obtained solid, Drying may be carried out by using suitable equipments. Drying may be carried out at suitable temperature with desired time periods.
In first aspect of third embodiment, the crystalline form of Oxetacaine of formula-1 obtained by the above process is characterized by its PXRD pattern substantially in accordance with figure-1.
In second aspect of third embodiment of the present invention provides a process for the preparation of crystalline form of Oxetacaine of formula-1, comprising:
a) dissolving Oxetacaine of formula-1 in ethanol and water mixture,
b) cooling the mixture obtained in step-a) to 0-5ºC,
c) filtering the crystalline form of Oxetacaine of formula-1.
In third aspect of third embodiment of the present invention provides a process for the preparation of crystalline form of Oxetacaine of formula-1, comprising:
a) dissolving Oxetacaine of formula-1 in acetone,
b) adding water to the solution obtained in step-a),
c) filtering the crystalline form of Oxetacaine of formula-1.
Powder X-ray power diffraction (PXRD) method of analysis:
PXRD analysis of the crystalline form of Oxetacaine is carried out by using
Bruker D8 advance X-ray powder diffractometer using Cu-Ka radiation of
wavelength 1.54060A° and at continuous scan speed of 0.033°/min.
High Performance Liquid Chromatography (HPLC) analysis method:
Oxetacaine and its related substances of present invention were analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: octadecylsilyl silica; 3 μm (or) equivalent; Wavelength: 210 nm; Flow rate: 1.0 mL/min; Injection volume: 10 μL; Elution: Gradient; Diluent: methanol.
Mobile phase A: 0.13 g of potassium dihydrogen phosphate in 1000 ml water. Adjust to a pH 2.4. Mobile phase-B: Acetonitrile.
The other embodiment of the present invention provides a method of treating a patients suffering pain associated with peptic ulcer disease or esophagitis comprising administering to the patients with a therapeutically effective amount of Oxetacaine obtained by the process of the present invention.
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.

Examples:
Example-1: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (30 g, 11.7 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 10.10 g (91.59%).
Example-2: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (5.1 g, 2 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 6.09 g (55.23%).
Example-3: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (10.2 g, 4 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 7.0 g (63.48%).
Example-4: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (17.90 g, 7 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 7.63 g (69.19%).
Example-5: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (25.5 g, 10 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 9.43 g (85.51%).
Example-6: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Sodium iodide (0.5 g, 0.07 mole equivalent), tetrabutyl ammonium bromide (0.7 g, 0.05 mole equivalent) and mono ethanolamine (30 g, 11.7 mole equivalent) were added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 6 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 10.16 g (92.16%).
Example-7: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (38.26 g, 15.01 mole equivalent) was added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent), n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 8.15 g (73.90%).
Example-8: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (36.45 g, 14.30 mole equivalent) were added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 12 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 9.11 g (82.61%).
Example-9: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (36.45 g, 14.30 mole equivalent) were added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent) and n-butanol (100 ml) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 14 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 8.90 g (80.71%).
Example-10: Preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxy ethyl)amino]-N-methylacetamide
Mono ethanolamine (42.14 g, 16.54 mole equivalent) were added to the mixture of 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide (10 g, 1 mole equivalent) n-butanol (100 ml) and sodium carbonate (10 g, 2.2 mole equivalent) at room temperature. Heated the reaction mixture to 120-125°C and stirred at same temperature for 14 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Organic layer was washed with water. Solvent was completely distilled off from the organic layer. n-Heptane was added to the above residue at 0-5°C and stirred for 10 minutes at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 8.31 g (75.36%).
Example-11: Preparation of Oxetacaine of formula-1
Sodium hydroxide (31 g, 2.04 mole equivalent) was added to the mixture of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methyl acetamide (100 g, 1.0 mole equivalent), 2-chloro-N-methyl-N-(2-methyl-1-phenyl propan-2-yl) acetamide (82 g, 0.9 mole equivalent) and toluene (500 ml) at room temperature. Heated the reaction mixture to 90-95°C and stirred at same temperature for 10 hours. Water was added to the reaction mixture and stirred for 10 minutes. Layer separated. Aqueous layer was extracted with toluene. Combine layers and washed with water. Organic layer was concentrated to become thick, cooled the concentrate to 0-5°C. The obtained solid was filtered and dried to get the pure compound.
Yield: 169.11 g (95.60%).
Example-12: Preparation of crystalline form of Oxetacaine
Oxetacaine (500 g) was dissolved in ethanol and water mixture at reflex temperature. Solution was cooled to 0-5°C. The obtained solid was filtered and dried to get the title compound.
Yield: 493.1 g (98.62%)
PXRD pattern of the above obtained compound is illustrated in figure-1.
Example-13: Preparation of crystalline form of Oxetacaine
Oxetacaine (500 g) was dissolved in acetone at reflex temperature. Water was added to the above solution and stirred for 10 minutes at room temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 495.75 g (99.15%)
PXRD pattern of the above obtained compound is same as figure-1. , Claims:I/We Claims:
1. A process for the preparation of N-(1,1-dimethyl-2-phenylethyl)-2-[(2-
hydroxyethyl)amino]-N-methylacetamide of formula-2, comprising: reacting 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide of formula-3 with mono ethanolamine to provide N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methylacetamide of formula-2

2. The process as claimed in claim 1, the above step is optionally carried out in a
solvent and a base selected from n-butanol and sodium carbonate respectively.
3. The process as claimed in claim 1, the amount of mono ethanolamine used in
the above reaction is ranges from 8 to 14 mole equivalent with respect to 2-chloro-N-(1,1-dimethyl-2-phenylethyl)-N-methylacetamide of formula-3.
4. A process for the preparation of Oxetacaine of formula-1, comprising: reacting
N-(1,1-dimethyl-2-phenylethyl)-2-[(2-hydroxyethyl)amino]-N-methyl acetamide of formula-2 with 2-chloro-N-methyl-N-(2-methyl-1-phenyl propan-2-yl) acetamide to provide Oxetacaine of formula-1

5. The process as claimed in claim 2, the above step is carried out in-presence of
a base and a solvent selected sodium hydroxide and toluene respectively.
6. A process for the preparation of crystalline form of Oxetacaine of formula-1, comprising:
a) dissolving Oxetacaine of formula-1 in a solvent,
b) isolating crystalline form of Oxetacaine of formula-1.

7. The process as claimed in claim 6, solvent used in step-a) selected from alcohol solvents or ketone solvents or any of the mixtures thereof.