Description:FIELD OF INVENTION
The present disclosure relates to a process for the synthesis of alpha lipoic acid.
BACKGROUND OF INVENTION
The background information herein below relates to the present disclosure but is not necessarily prior art.
Alpha lipoic acid is an important protein-bound coenzyme and growth factor found in plant and animal tissues as well as in microorganisms. It is recognized as a vital cofactor for the multi enzyme complexes which catalyze the oxidative decarboxylation of a-ketoacids such as pyruvate, a-ketoglutarate and the like. Alpha lipoic acid is found to be very effective in the treatment of severe liver disorders caused by Amanittaphalloides. It acts as a radioprotective agent which protects against ionizing radiation induced damage to DNA and its components. It shows cytoprotective effects on the gastric mucosa against ethanol aggression. One of the most important applications of lipoic acid is its ability to control diabetes. Recently, it has also been reported that lipoic acid and its derivatives show inhibitory effect against HIV replication and also act as antitumor agents. Apart from the above pharmacological importance, a-lipoic acid also finds its use in cosmetic preparations.
Alpha lipoic acid is synthesized by many conventional methods. The disadvantages of these methods are the use of highly toxic chemicals which are dangerous during operation and hazardous for the environment, long production cycles, poor product quality, and low yield of the product resulting in high production costs.
The literature is replete in various other methods for the synthesis of alpha lipoic acid by various routes. However, these methods are associated with drawbacks such as low yield and/ or low purity of alpha lipoic acid. Further, these methods require tedious purification steps, thereby resulting in an expensive process. Moreover, the conventional process for synthesis of alpha lipoic acid is not industrially feasible.
There is, therefore, felt a need to provide a process for the synthesis of alpha lipoic acid, which mitigates the drawbacks mentioned herein above or at least provides a useful alternative.
OBJECTS OF INVENTION
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present disclosure is to provide a process for the synthesis of alpha lipoic acid.
Another object of the present disclosure is to provide a simple, economical and environment-friendly process for the synthesis of alpha lipoic acid.
Still another object of the present disclosure is to provide a process for the synthesis of alpha lipoic acid with high purity and high yield.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY OF INVENTION
The present disclosure relates to a process for preparing alpha lipoic acid. The process comprises the step of reacting hexanedioic acid with methanol in the presence of sulphuric acid at a first predetermined temperature for a first predetermined time period to obtain an intermediate followed by base hydrolysis at a second predetermined temperature for a second predetermined time period to obtain 6-methoxy-6-oxohexanoic acid. 6-methoxy-6-oxohexanoic acid is chlorinated with thionyl chloride in a first fluid medium at a third predetermined temperature for a third predetermined time period to obtain methyl 6-chloro-6-oxohexanoate. Methyl 6-chloro-6-oxohexanoate is alkylated with ethylene gas in presence of catalyst in a second fluid medium in an inert atmosphere at a fourth predetermined temperature for a fourth predetermined time period to obtain methyl 8-chloro-6-oxooctanoate. Methyl 8-chloro-6-oxooctanoate is reduced by using a reducing agent in a third fluid medium at a fifth predetermined temperature for a fifth predetermined time period to obtain methyl 8-chloro-6-hydroxyoctanoate. Methyl 8-chloro-6-hydroxyoctanoate is further chlorinated with thionyl chloride in a fourth fluid medium at a sixth predetermined temperature for a sixth predetermined time period to obtain methyl 6,8-dichlorooctanoate. Methyl 6,8-dichlorooctanoate is reacted with sulphur powder in a fifth fluid medium in the presence of sodium sulfite at a seventh predetermined temperature for a seventh predetermined time period; purified using an extraction solvent to obtain alpha lipoic acid.
DETAILED DESCRIPTION OF INVENTION
The present disclosure relates to a process for the synthesis of alpha lipoic acid.
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Alpha lipoic acid is synthesized by many conventional methods. The disadvantages of these methods are the use of highly toxic chemicals which are dangerous during operation and hazardous for the environment, long production cycles, poor product quality, and low yield of the product resulting in high production costs.
The literature is replete in various other methods for the synthesis of alpha lipoic acid by various routes. However, these methods are associated with drawbacks such as low yield and/ or low purity of alpha lipoic acid. Further, these methods require tedious purification steps, thereby resulting in an expensive process. Moreover, the conventional process for synthesis of alpha lipoic acid is not industrially feasible.
The present disclosure provides a simple, economical and environment-friendly process for the synthesis of alpha lipoic acid. Alpha lipoic acid is represented by Formula I:

Formula (I)
The process for preparing alpha lipoic acid comprises the following steps:
i. reacting hexane dioic acid with methanol in presence of sulphuric acid at a first predetermined temperature for a first predetermined time period to obtain an intermediate followed by base hydrolysis at a second predetermined temperature for a second predetermined time period to obtain 6-methoxy-6-oxohexanoic acid;
ii. chlorinating 6-methoxy-6-oxohexanoic acid with thionyl chloride in a first fluid medium at a third predetermined temperature for a third predetermined time period to obtain methyl-6-chloro-6-oxohexanoate;
iii. alkylating methyl-6-chloro-6-oxohexanoate with ethylene gas in presence of catalyst in a second fluid medium in an inert atmosphere at a fourth predetermined temperature for a fourth predetermined time period to obtain methyl-8-chloro-6-oxooctanoate;
iv. reducing methyl-8-chloro-6-oxooctanoate by using a reducing agent in a third fluid medium at a fifth predetermined temperature for a fifth predetermined time period to obtain methyl 8-chloro-6-hydroxyoctanoate;
v. chlorinating methyl-8-chloro-6-hydroxyoctanoate with thionyl chloride in a fourth fluid medium at a sixth predetermined temperature for a sixth predetermined time period to obtain methyl-6,8-dichlorooctanoate; and
vi. reacting methyl-6,8-dichlorooctanoate with sulphur powder in a fifth fluid medium in the presence of sodium sulfiteat a seventh predetermined temperature for a seventh predetermined time period to obtain alpha lipoic acid.
The process for preparing alpha lipoic acid is described in detail herein below.
Step (i): Preparation of 6-methoxy-6-oxohexanoic acid
In a first step, hexane dioic acid is reacted with methanol in the presence of sulphuric acid at a first predetermined temperature for a first predetermined time period to obtain an intermediate followed by base hydrolysis at a second predetermined temperature for a second predetermined time period to obtain 6-methoxy-6-oxohexanoic acid.
In accordance with the present disclosure, the first predetermined temperature is in the range of 60 °C to 80 °C.In an exemplary embodiment of the present disclosure, the first predetermined temperature is 70 °C.
In accordance with the present disclosure, the first predetermined time period is in the range of 2 hours to 5 hours.In an embodiment of the present disclosure, the first predetermined time period is in the range of 3-4 hours.
In accordance with the present disclosure, the second predetermined temperature is in the range of 20 °C to 40 °C.In an exemplary embodiment of the present disclosure, the second predetermined temperature is 30 °C.
In accordance with the present disclosure, the second predetermined time period is in the range of 2 hours to 6 hours.In an embodiment of the present disclosure, the second predetermined time period is in the range of 2 hours to 6 hours.
The preparation of 6-methoxy-6-oxohexanoic acid, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(a)given below:

Scheme 1(b): Schematic representation of the preparation of 6-methoxy-6-oxohexanoic acid
Step (ii) Preparation of methyl-6-chloro-6-oxohexanoate:
In a second step,6-methoxy-6-oxohexanoic acid is chlorinated with thionyl chloride in a first fluid medium at a third predetermined temperature for a third predetermined time period to obtain methyl-6-chloro-6-oxohexanoate.
In accordance with the present disclosure, the first fluid medium is an alcohol solvent, more particularly dichloromethane.
In accordance with the present disclosure, the third predetermined temperature is in the range of 40 °C to 50 °C.In an exemplary embodiment of the present disclosure, the third predetermined temperature is 45 °C.
In accordance with the present disclosure, the third predetermined time period is in the range of 2 hours to 8 hours.In an embodiment of the present disclosure, the third predetermined time period is in the range of 3-4 hours.
The preparation of methyl-6-chloro-6-oxohexanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(b)given below:

Scheme 1(b): Schematic representation of the preparationof methyl-6-chloro-6-oxohexanoate
Step (iii): Preparation of methyl 8-chloro-6-oxooctanoate
In a third step, methyl-6-chloro-6-oxohexanoate is alkylated with ethylene gas in presence of catalyst in a second fluid medium in an inert atmosphere at a fourth predetermined temperature for a fourth predetermined time period to obtain methyl-8-chloro-6-oxooctanoate.
In accordance with the present disclosure, the fourth predetermined temperature is in the range of 0°C to 15°C.In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 10 °C.
In accordance with the present disclosure, the second fluid medium isselected from group consisting of aluminium chloride, titanium tetrachloride, lithium chloride and dichloromethane or any combinations thereof.
In accordance with the present disclosure, the fourth predetermined time period is in the range of 2 hours to 10 hours.In an embodiment of the present disclosure, the fourth predetermined time period is in the range of 3-5 hours.
The preparation ofmethyl-8-chloro-6-oxooctanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(c)given below:

Scheme 1(c): Schematic representation of the preparation of methyl-8-chloro-6-oxooctanoate
Step (iv): Preparation of methyl 8-chloro-6-hydroxyoctanoate
In a fourth step, methyl 8-chloro-6-oxooctanoate is reduced by using a reducing agent in a third fluid medium at a fifth predetermined temperature for a fifth predetermined time period to obtain methyl 8-chloro-6-hydroxyoctanoate.
In accordance with the present disclosure, the fifth predetermined temperature is in the range of 0 °C to 10 °C.In an exemplary embodiment of the present disclosure, the fifth predetermined temperature is 5 °C.
In accordance with the present disclosure, the fifth predetermined time period is in the range of 1hours to 5 hours. In an embodiment of the present disclosure, the fifth predetermined time period is in the range of 2-3 hours.
The preparation of methyl 8-chloro-6-hydroxyoctanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(d)given below:

Scheme 1(d): Schematic representation of the preparation of methyl 8-chloro-6-hydroxyoctanoate
Step (v): Preparation of methyl-6, 8-dichlorooctanoate
In a fifth step, methyl 8-chloro-6-hydroxyoctanoate is further chlorinated with thionyl chloride in a fourth fluid medium at a sixth predetermined temperature for a sixth predetermined time period to obtain methyl-6,8-dichlorooctanoate.
In accordance with the present disclosure, the fourth fluid medium is selected from group consisting of toluene and methylene dichloride or any combinations thereof.
In accordance with the present disclosure, the sixth predetermined temperature is in the range of 40°C to 95°C.In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 50-80 °C.
In accordance with the present disclosure, the sixth predetermined time period is in the range of 2 hours to 10 hours.In an embodiment of the present disclosure, the fourth predetermined time period is in the range of 3-5 hours.

The synthesis of methyl-6,8-dichlorooctanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(e)given below:

Scheme 1(e): Schematic representation of the preparation of methyl-6,8-dichlorooctanoate

Step (vi): Preparation of 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid)
In a sixth step, methyl 6,8-dichlorooctanoate is reacted with sulphur powder in a fifth fluid medium in the presence of sodium sulfite at a seventh predetermined temperature for a seventh predetermined time period; purified using an extraction solvent to obtain alpha lipoic acid.
In accordance with the present disclosure, the fifth fluid medium is selected from group consisting of toluene and methylene dichloride or any combinations thereof.
In accordance with the present disclosure, the seventh predetermined temperature is in the range of 60°C to 80°C.In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 65-70 °C.
In accordance with the present disclosure, the seventh predetermined time period is in the range of 2 hours to 6 hours.In an embodiment of the present disclosure, the fourth predetermined time period is in the range of 3-5 hours.
1. In accordance with the present disclosure, the extraction medium used for purification is a mixture of at least two mediums selected from group consisting of ethyl acetate, cyclohexane, acetone, hexane isopropyl alcohol, methanol or any combinations thereof.In an embodiment of the present disclosure, the extraction solvents combinations are selected from cyclohexane: ethyl acetate, cyclohexane: acetone , hexane: acetone, cyclohexane: IPA, cyclohexane: methanol.
The preparation of alpha lipoic acid, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1(f)given below:

Scheme 1(f): Schematic representation of the preparation of alpha lipoic acid
The process of the present disclosure employs inexpensive and easily available reagents. Thus, the process of the present disclosure is economical.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.
EXPERIMENTAL DETAILS
Preparation of alpha lipoic acid in accordance with the present disclosure
i. Preparation of 6-methoxy-6-oxohexanoic acid
Hexane dioic acid (50 g, 0.34 mole) was dissolved in 100 ml methanol, added sulphuric acid (0.8 g, 0.0023 mole), and heat the reaction mixture to 65-70°C for 3-4hrs, cool the reaction mass to room temperature and sodium hydroxide (14.9 g, 0.36 mole) in 50 ml methanol, distilled out methanol completely and add 100 ml water, separate the upper organic layer. Adjust pH of aqueous layer using con. HCl to 0-1, by adding 100 ml toluene, filter solid obtained. Further aq. layer extracted with 100toluene, on complete distillation of solvent gives28 g 6-methoxy-6-oxohexanoic acid as oil, Purity 99.0%.
ii. Preparation of methyl 6-chloro-6-oxohexanoate

6-methoxy-6-oxohexanoic acid (28 g, 0.17 mole) dissolved in 560 ml MDC, added thionyl chloride (23.9 g, 0.2 mole) and heat the reaction mass to 40-45°C for 4-6 hrs, on complete distillation of solvent gives 28.2 g of methyl 6-chloro-6-oxohexanoate,Purity 99.0%.
iii. Preparation of methyl 8-chloro-6-oxooctanoate

Example-3.1

A suspension of aluminium chloride (48.1 g, 0.35 mole) in 125 ml dichloromethane under nitrogen, added solution of methyl 6-chloro-6-oxohexanoate (31.3 g, 0.17 mole) in 31.1 ml dichloromethane at 10-15°C. The reaction mixture was stirred for 2-4 hrs, purge ethylene gas (5.5 g, 0.19 mole), stir the reaction mass for 2 hr and quench the reaction mass in ice cold water. The resulting aqueous layer extracted with 31.1 ml dichloromethane, on complete distillation of solvent under vacuum gives 34.6 (96.13% yield) g of methyl 8-chloro-6-oxooctanoate, Purity NLT85%.
Example-3.2

A suspension of aluminium chloride (48.1 g, 0.35 mole) and Titanium tetrachloride 1.56 g in 125 ml dichloromethane under nitrogen, added solution of methyl 6-chloro-6-oxohexanoate (31.3 g, 0.17 mole) in 31.1 ml dichloromethane at 0-10°C. The reaction mixture was stirred for 2-4 hrs, purge ethylene gas (5.5 g, 0.19 mole), stir the reaction mass for 4-6hr and quench the reaction mass in ice cold water. The resulting aqueous layer extracted with 31.1 ml dichloromethane, on complete distillation of solvent under vacuum gives 33.8 to 35.2 g (93.91% to 97.80%) of methyl 8-chloro-6-oxooctanoate, Purity NLT 90%.
Example-3.3

A suspension of aluminium chloride (48.1 g, 0.35 mole) and Lithium chloride 1.56 g in 125 ml dichloromethane under nitrogen, added solution of methyl 6-chloro-6-oxohexanoate (31.3 g, 0.17 mole) in 31.1 ml dichloromethane at 0-10°C. The reaction mixture was stirred for 2-4 hrs, purge ethylene gas (5.5 g, 0.19 mole), stir the reaction mass for 6-8hr and quench the reaction mass in ice cold water. The resulting aqueous layer extracted with 31.1 ml dichloromethane, on complete distillation of solvent under vacuum gives 33.8 g (93.91% yield) of methyl 8-chloro-6-oxooctanoate, Purity NLT 90%.
iv. Preparation of methyl 8-chloro-6-hydroxyoctanoate
A solution of methyl 8-chloro-6-oxooctanoate (33.5 g, 0.17 mole) in 67 ml methanol was cool to 0-5°C, sodium borohydride (1.97 g, 0.052 mole) added over a period of 2-3 hrs, stir the reaction mass for 1-2 hrs. The resulting reaction mass was quench in ice cold water, adjust pH pf reaction mass to 4-5 using acetic acid, followed by extraction in 67 ml dichloromethane, on complete distillation of solvent under vacuum gives 32.05 g of (95.7% yield) methyl 8-chloro-6-hydroxyoctanoate, Purity NLT 86%.
v. Preparation of methyl 6,8-dichlorooctanoate

Example-5.1

A solution of methyl 8-chloro-6-hydroxyoctanoate (30 g, 0.15 mole) in 60 ml toluene was added in thionyl chloride (21.9 g, 0.18 mole) at 50-55°C. After complete addition stir the reaction mass at 80-85°C for 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature and wash the toluene layer with 60 ml water. Distilled out the reaction solvent under vacuum give dark brown colour oil, purity 75%. The resulting compound on high vacuum distillation at 0.1 mm/Hg gives 17.2 g of methyl 6,8-dichlorooctanoate, light yellow colour oil, purity NLT 95.00%
Example-5.2

A solution of methyl 8-chloro-6-hydroxyoctanoate (30 g, 0.15 mole) in 60 ml MDC was added in thionyl chloride (21.9 g, 0.18 mole) at 40-42°C. After complete addition stir the reaction mass at 40-42°C for 6-10 hrs. After completion of the reaction the reaction mixture was cooled to room temperature and wash the MDC layer with 60 ml water. Distilled out the reaction solvent under vacuum give dark brown colour oil, purity 78%. The resulting compound on high vacuum distillation at 0.1 mm/Hg gives 17.2 g of methyl 6,8-dichlorooctanoate, light yellow colour oil, purity NLT 95.00%
vi. Preparation of 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid)
Example-6.1

A solution of methyl 6,8-dichlorooctanoate (16.5 g, 0.072 mole) in 165 ml methanol, was treated with sodium hydroxide (3.5 g, 0.087 mole) in 11 ml water. The reaction mixture was heated to 65-70°C for 4-5 hrs, after completion of the reaction the solvent was distilled out under vacuum at 50-55°C. The resulting residue was treated with sulphur powder (5.56 g, 0.08 mole) in 66 ml methanol at 65-70°C, added sodium sulphide (8.2 g, 0.72 mole) and stir the reaction mass for 3-4 hrs. Further, added Sodium sulfite (12.9 g, 0.10 mole) at 75-80°C, and maintained for about 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature. The resulting reaction mass was quench in 330 ml water, adjust pH of reaction mass to 4-5 using acetic acid. The aqueous reaction mass was extracted with 25% solution 330 ml (Ethyl acetate: Cyclohexane), after complete distillation of solvent gives crude 5-(1,2-dithiolan-3-yl) pentanoic acid. Further, 5-(1,2-dithiolan-3-yl) pentanoic acid on recrystallization in ethyl acetate: cyclohexane mixture gives 90.5 g pure 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid), Purity NLT 99.9%

Example-6.2

A solution of methyl 6,8-dichlorooctanoate (16.5 g, 0.072 mole) in 165 ml methanol, was treated with sodium hydroxide (3.5 g, 0.087 mole) in 11 ml water. The reaction mixture was heated to 65-70°C for 4-5 hrs, after completion of the reaction the solvent was distilled out under vacuum at 50-55°C. The resulting residue was treated with sulphur powder (5.56 g, 0.08 mole) in 66 ml methanol at 65-70°C, added sodium sulphide (8.2 g, 0.72 mole) and stir the reaction mass for 3-4 hrs. Further, added Sodium sulfite (12.9 g, 0.10 mole) at 75-80°C, and maintained for about 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature. The resulting reaction mass was quench in 330 ml water, adjust pH of reaction mass to 4-5 using acetic acid. The aqueous reaction mass was extracted with 25% solution (acetone: Cyclohexane), after complete distillation of solvent gives crude 5-(1,2-dithiolan-3-yl) pentanoic acid. Further, 5-(1,2-dithiolan-3-yl) pentanoic acid on recrystallization in actone: cyclohexane mixture gives 90.5 g pure 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid), Purity 99.9%

Example-6.3

A solution of methyl 6,8-dichlorooctanoate (16.5 g, 0.072 mole) in 165 ml methanol, was treated with sodium hydroxide (3.5 g, 0.087 mole) in 11 ml water. The reaction mixture was heated to 65-70°C for 4-5 hrs, after completion of the reaction the solvent was distilled out under vacuum at 50-55°C. The resulting residue was treated with sulphur powder (5.56 g, 0.08 mole) in 66 ml methanol at 65-70°C, added sodium sulphide (8.2 g, 0.72 mole) and stir the reaction mass for 3-4 hrs. Further, added Sodium sulfite (12.9 g, 0.10 mole) at 75-80°C, and maintained for about 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature. The resulting reaction mass was quench in 330 ml water, adjust pH of reaction mass to 4-5 using acetic acid. The aqueous reaction mass was extracted with 25% solution (hexane: acetone), after complete distillation of solvent gives crude 5-(1,2-dithiolan-3-yl) pentanoic acid. Further, 5-(1,2-dithiolan-3-yl) pentanoic acid on recrystallization in hexane: acetone mixture gives 90.5 g pure 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid), Purity 99.9%

Example-6.4

A solution of methyl 6,8-dichlorooctanoate (16.5 g, 0.072 mole) in 165 ml methanol, was treated with sodium hydroxide (3.5 g, 0.087 mole) in 11 ml water. The reaction mixture was heated to 65-70°C for 4-5 hrs, after completion of the reaction the solvent was distilled out under vacuum at 50-55°C. The resulting residue was treated with sulphur powder (5.56 g, 0.08 mole) in 66 ml methanol at 65-70°C, added sodium sulphide (8.2 g, 0.72 mole) and stir the reaction mass for 3-4 hrs. Further, added Sodium sulfite (12.9 g, 0.10 mole) at 75-80°C, and maintained for about 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature. The resulting reaction mass was quench in 330 ml water, adjust pH of reaction mass to 4-5 using acetic acid. The aqueous reaction mass was extracted with 25% solution (cyclohexane: isopropyl alcohol), after complete distillation of solvent gives crude 5-(1,2-dithiolan-3-yl) pentanoic acid. Further, 5-(1,2-dithiolan-3-yl) pentanoic acid on recrystallization in cyclohexane: isopropyl alcohol mixture gives 90.5 g pure 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid), Purity 99.9%

Example-6.5

A solution of methyl 6,8-dichlorooctanoate (16.5 g, 0.072 mole) in 165 ml methanol, was treated with sodium hydroxide (3.5 g, 0.087 mole) in 11 ml water. The reaction mixture was heated to 65-70°C for 4-5 hrs, after completion of the reaction the solvent was distilled out under vacuum at 50-55°C. The resulting residue was treated with sulphur powder (5.56 g, 0.08 mole) in 66 ml methanol at 65-70°C, added sodium sulphide (8.2 g, 0.72 mole) and stir the reaction mass for 3-4 hrs. Further, added Sodium sulfite (12.9 g, 0.10 mole) at 75-80°C, and maintained for about 3-5 hrs. After completion of the reaction the reaction mixture was cooled to room temperature. The resulting reaction mass was quench in 330 ml water, adjust pH of reaction mass to 4-5 using acetic acid. The aqueous reaction mass was extracted with 25% solution (cyclohexane: methanol), after complete distillation of solvent gives crude 5-(1,2-dithiolan-3-yl) pentanoic acid. Further, 5-(1,2-dithiolan-3-yl) pentanoic acid on recrystallization in cyclohexane: methanol mixture gives 90.5 g pure 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid), Purity 99.8%.

The yield and purity of 5-(1,2-dithiolan-3-yl) pentanoic acid (Alpha lipoid acid) obtained using above process is summarized below in table 1

Table 1: Efficiency and purity of process for synthesis of alpha lipoic acid
Example Yield % Purity %
Example 6.1 90 99.9
Example 6.2 95 99.9
Example 6.3 94 99.9
Example 6.4 91 99.9
Example 6.5 96 99.8

From above, it is conclusive that the above process step along with the process parameter such as temperature range and purification solvent played an effective role achieving higher yield and purity.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the synthesis of 4-methyl sulfonyl toluene, which:
- is carried out at low pressure;
- is feasible for large scale manufacturing;
- is simple, economical and environment-friendly; and
- provides high yield and high purity 4-methyl sulfonyl toluene.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation. , Claims:WE CLAIM:
1. A process for preparing alpha lipoic acid, said process comprising the following steps:
i. reacting hexanedioic acid with methanol in presence of sulphuric acid at a first predetermined temperature for a first predetermined time period to obtain an intermediate followed by base hydrolysis at a second predetermined temperature for a second predetermined time period to obtain 6-methoxy-6-oxohexanoic acid;
ii. chlorinating 6-methoxy-6-oxohexanoic acid with thionyl chloride in a first fluid medium at a third predetermined temperature for a third predetermined time period to obtain methyl 6-chloro-6-oxohexanoate;
iii. alkylatingmethyl 6-chloro-6-oxohexanoate with ethylene gas in presence of catalyst in a second fluid medium in an inert atmosphere at a fourth predetermined temperature for a fourth predetermined time period to obtain methyl 8-chloro-6-oxooctanoate;
iv. reducing methyl 8-chloro-6-oxooctanoate by using a reducing agent in a third fluid medium at a fifth predetermined temperature for a fifth predetermined time period to obtain methyl 8-chloro-6-hydroxyoctanoate;
v. chlorinating methyl 8-chloro-6-hydroxyoctanoate with thionyl chloride in a fourth fluid medium at a sixth predetermined temperature for a sixth predetermined time period to obtain methyl 6,8-dichlorooctanoate; and
vi. reacting methyl 6,8-dichlorooctanoate with sulphur powder in a fifth fluid medium in the presence of sodium sulphite at a seventh predetermined temperature for a seventh predetermined time period; purified using an extraction solvent to obtain alpha lipoic acid.
2. The process as claimed in claim 1, wherein said first fluid medium is dichloromethane.
3. The process as claimed in claim 1, wherein said second fluid medium is selected from group consisting of aluminium chloride, titanium tetrachloride, lithium chloride and dichloromethane or any combinations thereof.
4. The process as claimed in claim 1, wherein said thirdfluid medium and said fifth fluid medium is methanol.
5. The process as claimed in claim 1, wherein said fourth fluid medium is selected from toluene and methylene dichloride.
6. The process as claimed in claim 1, wherein said extraction medium is mixture of at least two mediums selected from group consisting of ethyl acetate, cyclohexane, acetone, hexane isopropyl alcohol, methanol or any combinations thereof.
7. The process as claimed in claim 1, wherein said;
? first predetermined temperature is in the range of 60 °C to 80°C;
? second predetermined temperature is in the range of 20°C to 40°C;
? third predetermined temperature is in the range of 40°C to 50°C;
? fourth predetermined temperature is in the range of 0°C to 15°C;
? fifth predetermined temperature is in the range of 0°C to 10°C;
? sixth predetermined temperature is in the range of 40°C to 95°C; and
? seventh predetermined temperature is in the range of 60°C to 80°C.
8. The process as claimed in claim 1, wherein said;
? first predetermined time period is in the range of 2 hours to 5 hours;
? second predetermined time period is in the range of 2 hours to 6 hours;
? third predetermined time period is in the range of 3 hours to 8 hours;
? fourth predetermined time period is in the range of 2 hour to 10 hours;
? fifth predetermined time period is in the range of 1 hours to 5 hours;
? sixth predetermined time period is in the range of 2 hours to 10 hours; and
? seventh predetermined time period is in the range of 2 hours to 6 hours.
9. The process as claimed in claim 1, wherein said catalyst is selected from aluminium chloride, titanium tetrachloride, lithium chloride and a combination thereof.
10. The process as claimed in claim 1, wherein said step (iv) of reducing methyl 8-chloro-6-oxooctanoate comprises the following sub-steps:
(a) cooling a solution of methyl 8-chloro-6-oxooctanoate in methanol to a temperature in the range of 0 °C to 5 °C to obtain a cooled solution;
(b) gradually adding a reducing agent over a time period in the range of 2 hours to 4 hours to obtain a reaction mass; and
(c) stirring said reaction mass for a time period in the range of 1 hour to 3 hours to obtain a resultant mass followed by quenching said resultant mass in ice cold water having temperature in the range of 0 °C to 5 °C and adjusting pH in the range of 4 to 6 using acetic acid to obtain a product mass comprising methyl 8-chloro-6-hydroxyoctanoate.
11. The process as claimed in claims 1 and 6, wherein said reducing agent is sodium borohydride.