DESC:As used herein, the terms below have the meanings indicated.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about" as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

In the first embodiment the present invention provides an improved process for the preparation of highly pure (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I

comprises:
a) esterification of adipic acid of the formula II with methanol in the presence of a acid and suitable organic solvent to obtain 6-methoxy-6-oxohexanoic acid of the formula III;

b) 6-methoxy-6-oxohexanoic acid of the formula III is converted to methyl-6-chloro-6-oxohexanoate of the formula IV by reacting with SOCl2 in toluene, and it is further reacted with ethylene in presence of AlCl3 and organic solvent to obtain methyl 8-chloro-6-oxoocatnoate of the formula V;

c) reduction of methyl 8-chloro-6-oxoocatnoate of the formula V in presence of reducing agent and organic solvent to obtain methyl 8-chloro-6-hydroxyoctanoate of the formula VI;

d) methyl 8-chloro-6-hydroxyoctanoate of the formula VI is treated with thionyl chloride in presence of organic solvent to obtain methyl 6,8-dichloroocatnoate of the formula VII;

e) methyl 6,8-dichloroocatnoate of the formula VII reacts with disodium sulfide, sulphur powder in presence of phase transfer catalyst to obtain methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII;

f) reduction of methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII in presences of reducing agent to obtain Dihydro Lipoic acid of the formula IX which is further reacted in the presence of catalytic amounts of iron(III), to obtain (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I;

According to another embodiment, there is provided a process for the preparation of 6-methoxy-6-oxohexanoic acid of the formula III in high purity and better yields by the esterification of adipic acid of the formula II with methanol in the presence of an acid and suitable organic solvent to obtain 6-methoxy-6-oxohexanoic acid of the formula III;

Specifically the reaction is conducted at 25°C-90°C in organic solvent for about 2-10 hours for completion of reaction.

The 6-methoxy-6-oxohexanoic acid of the formula III was purified to remove impurity.

According to above embodiment, organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof. In embodiments, the solvent is selected from pentane, hexane, heptane cyclohexane, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate toluene, xylene, ethyl benzene, heptane, hexane, cyclohexane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, carbontetrachloride, 1,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, ethylene chloride, and combinations thereof.

According to above embodiment, acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or boric acid.

According to another embodiment, there is provided a process for the preparation of methyl 8-chloro-6-oxoocatnoate of the formula V comprising reacting 6-methoxy-6-oxohexanoic acid of the formula III with SOCl2 in toluene to methyl-6-chloro-6-oxohexanoate of the formula IV, and it is further reacted with ethylene in presence of AlCl3 and solvent to obtain methyl 8-chloro-6-oxoocatnoate of the formula V;

According to another embodiment, there is provided a process for the preparation of methyl 8-chloro-6-hydroxyoctanoate of the formula VI comprising reduction of methyl 8-chloro-6-oxoocatnoate of the formula V in presence of reducing agent and organic solvent to obtain methyl 8-chloro-6-hydroxyoctanoate of the formula VI;

According to above embodiment, organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof. In embodiments, the solvent is selected from pentane, hexane, heptane cyclohexane, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate toluene, xylene, ethyl benzene, heptane, hexane, cyclohexane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, carbontetrachloride, 1,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, ethylene chloride, and combinations thereof.

According to another embodiment, there is provided a process for the preparation of methyl 6,8- dichloroocatnoate of the formula VII comprising methyl 8-chloro-6-hydroxyoctanoate of the formula VI is treated with thionyl chloride in presence of organic solvent to obtain methyl 6,8-dichloroocatnoate of the formula VII;

In various embodiments, the solvent is selected from but not limited to ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane, and combinations thereof.

According to another embodiment, there is provided a process for the preparation of methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII comprising reaction of methyl 6,8-dichloroocatnoate of the formula VII with disodium sulfide, sulphur powder in presence of phase transfer catalyst to obtain methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII.

According to above embodiment, phase-transfer catalyst is a quaternary ammonium salt such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide (TBAB), and methyltri-n-octylammonium chloride. Most preferable phase-transfer catalyst is Tetrabutylammonium halides, such as tetrabutylammonium bromide (TBAB).

According to above embodiment, organic solvent comprises ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof. In embodiments, the solvent is selected from pentane, hexane, heptane cyclohexane, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate toluene, xylene, ethyl benzene, heptane, hexane, cyclohexane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, carbontetrachloride, 1,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, ethylene chloride, and combinations thereof.

According to another embodiment, there is provided a process for the preparation of (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I comprising reduction of methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII in presences of reducing agent to obtain Dihydro Lipoic acid of the formula IX which is further reacted in the presence of catalytic amounts of iron(III), to obtain (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I

EXAMPLE 1: Process for preparation of Monomethyl Adipate from Adipic Acid (Formula III)
Charge Adipic acid (1000 g), Methanol (277.2 g) and Conc. HCl(90ml). Stir the reaction mass at 80-85? for 6-8 hrs. Cool the reaction mass at 25-35?. Charge toluene(1500ml) and cool the mixture at 0-5?. Stir the above mixture at 0-5? for 30-60 min. Filter the mixture and wash with toluene (250ml x 2). Dry the obtained product for 5-6 hrs. (Yield-41%, Purity-98.0%)
EXAMPLE 2: Process for preparation of Methyl 8-chloro 6-oxoctanoate (Formula V):
Add thionyl chloride(274g) into monomethyl adipate(335g). Heat the above mixture at 80-90?. Maintain the reaction mass at 80-90? for 2 hrs. Distill out thionyl chloride under vacuum. Cool the reaction mass and MDC (1507ml) and Aluminum chloride (500 g) in 3 lots. Stir the mixture for 30-60 min. Purge ethylene gas and cool the reaction mass. Mix crushed ice(3000g) at 0-10? and heat the mixture at 20-30?. Stir the reaction mass for 30-60 min. Settle and separate the mixture. Collect aq.layer and charge MDC (167.5ml).Stir the mixture for 30-60 min. Settle and separate the layers. Collect both organic layer and charge RO water(770ml). Stir the mixture for 30-60 min. Settle and separate the layers. Collect organic layer and add 5% NaHCO3 solution (1000 ml). Stir the mixture for 30-60 min. Settle and separate the layers. Collect organic layer and distill out under vacuum to obtain product. (Yield-80%, Purity-98.58%)
EXAMPLE 3: Process for preparation of Methyl 8-chloro 6-hydroxyoctanoate (Formula-VI):
Mix Toluene (450 ml) and methyl 8-chloro 6-oxoctanoate (300 g). Cool the mixture 0-5? and add methanol (150 ml) and sodium borohydride (23.16 g) in 12 lot. Stir the reaction mass for 15 -20 min. Heat the mixture at 35-40? and stir for 2-3 hrs. Cool the mixture at 0-5? and add RO water (1650 ml). Stir the reaction mass for 15-20 min. Adjust pH 4.0 to 5.0 using 50% dil. HCl solution. Heat the reaction mass at 25-35 ? and stir the mixture for 15-20 min. Settle and separate the mixture. Collect aq. Layer and charge toluene (150 ml). Stir the mixture for 25-30 min. Settle and separate the layers. Collect both organic layer and add RO water (300 ml). Stir the mixture for 25-30 min. Settle and separate the layers. Collect the organic layer and distill out under vacuum to obtain product. (Yield-97.78%, Purity-98.86%)
EXAMPLE 4: Process for preparation of Methyl 6,8- dichlorooctanoate (Formula-VII)
Mix MDC (600 ml) and Thionyl Chloride (205.25 g) at 0-5?. Add TEA solution at 0-5?. Add methyl 8-chloro 6-hydroxyoctanoate solution at 0-5?. Heat the reaction mass at 37-42?. Stir the mixture for 2-3 hrs. Slowly Cool the mixture at 0-5?. Add chilled RO water (1500 ml). Heat the mixture at 25-35?. Stir the reaction mass at 15-20 min. Settle and separate the layers. Collect aq. Layer and charge MDC (150 ml) and stir for 25-30 min. Settle and separate the layers. Combine both organic layers and add RO water (600 ml). Stir the mixture for 25-30 min and settle and separate the layers. Collect organic layer and add RO water (300 ml) and stir the mixture for 25-30 min. Settle and separate the layers. Collect organic layer and distill out under vacuum to get product. (Yield-89.2%, Purity-99.25%)
EXAMPLE 5: Process for preparation of methyl 5-(1, 2-dithiolan-3-yl) pentanoate (Formula-VIII)
Mix Sodium sulfide (60 g), RO water (200 ml) and sulfur powder (15 g). Heat the mixture at 80-85?. Maintain the reaction mass at 80-85? for 2-3 hrs. Cool the reaction mass at 20-30? and stir for 15-20 min and filter the reaction mass. In a separate 2.0 Liter four-neck flask, 100 g of LPC-05, 200 ml of toluene, and (4 g) of tetrabutylammonium bromide are charged at 25-35°C. This second flask is heated to 80-85°C, and the filtered reaction mass from the first step is added over 3-4 hours. The temperature is then raised to 87-92°C and held for 1 hour. A sample of the upper organic layer is submitted for HPLC analysis at 85-90°C. After cooling to 25-35°C and settling for 25-30 minutes, the upper organic product layer is separated from the lower aqueous layer. The aqueous layer is extracted with (200 ml) toluene, and the resulting organic layer is combined with the previous organic layer. This combined organic layer is washed with (200 ml) water, settled, and the upper product-containing organic layer is separated. Toluene is then distilled off under vacuum at 45-50°C. The distilled residue is degassed under vacuum at 45-50°C to get product.
EXAMPLE 6: Process for preparation of 5-(1,2-dithiolan-3-yl) pentanoic acid (Formula-IX)
Mix RO water and methyl 5-(1,2-dithiolan-3-yl)pentanoate. After cooling to 0-10°C, a borol solution (prepared from water, sodium hydroxide, and sodium borohydride) is added over 30 minutes. The temperature is raised to 45-50°C and maintained for 2 hours, and add NaOH (3.6 g x 5) in every 1-2 hours. After reaction complies cool the reaction mass at 25-35°C. Add toluene, and the pH is adjusted to 9.25-9.75 with hydrochloric acid. The aqueous product layer is separated, extracted with toluene, and the combined organic layers are washed with water. The product is then extracted into toluene by adjusting the pH to 2.75-3.25 at 5-15°C. Heat the mixture at 30-40°C, the toluene organic layer containing product is separated washed with water, and the pH is adjusted to 8.5-9.0 with sodium hydroxide solution at 0-10°C to give the aqueous product layer. Air purge into the reaction mass for 3-4 hrs. After reaction complies charge toluene and stir the mixture 15-20 min and filter the reaction mass. Collect filtrate and add toluene layer and NaoH (3.6g). Stir the reaction mass for 15-30 min and settle and separate the layers. Charge cyclohexane (500 ml) and adjust the pH at 3.75-4.25 at 5-10°C. Stir the mixture for 25-30 min and filter. The wet cake is dried at 40-45°C, slurried in toluene/cyclohexane at 70-80°C, filtered through a silica bed, and the solid final product is dried under vacuum at 40-50°C.(Yield-95.2% , Purity-99.95%)
,CLAIMS:I/We Claim,

1.) A process for preparation of alpha lipoic acid formula I comprises;

a.) esterification of adipic acid of the formula II with methanol in the presence of acid and suitable organic solvent to obtain 6-methoxy-6-oxohexanoic acid of the formula III;
b.) 6-methoxy-6-oxohexanoic acid of the formula III is converted to methyl-6-chloro-6-oxohexanoate of the formula IV by reacting with SOCl2 in toluene, and it is further reacted with ethylene in presence of AlCl3 and organic solvent to obtain methyl 8-chloro-6-oxoocatnoate of the formula V;
c.) reduction of methyl 8-chloro-6-oxoocatnoate of the formula V in presence of reducing agent and organic solvent to obtain methyl 8-chloro-6-hydroxyoctanoate of the formula VI;
d.) methyl 8-chloro-6-hydroxyoctanoate of the formula VI is treated with thionyl chloride in presence of organic solvent to obtain methyl 6,8-dichloroocatnoate of the formula VII;
e.) methyl 6,8-dichloroocatnoate of the formula VII reacts with disodium sulfide, sulphur powder in presence of phase transfer catalyst to obtain methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII;

f.) reduction of methyl 5-(1,2-dithiolan-3-yl) pentanoate of the formula VIII in presences of reducing agent to obtain Dihydro Lipoic acid of the formula IX which is further reacted in the presence of catalytic amounts of iron(III);
g.) purge air into the reaction until reaction complies;
h.) after reaction complies charge toluene and stir for 15-20 min at 25-35?;
i.) filter the reaction mass and wash with water;
j.) Collect toluene ml and charge sodium hydroxide;
k.) Stir for 30-60 min at 25-35? and settle and separate the mixture;
l.) Collect aq.layer and charge cyclohexane and cool the mixture at 5-10 ?;
m.) Adjust pH 3.75 to 4.25 using 50% HCl solution at 5-10 ? and stir for 30-60 min;
n.) Filter the reaction mass wash with water and cyclohexane ;
o.) Dry the material to obtain (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I;
2.) A process for the purification of alpha lipoic acid of Formula I comprising;
a.) Dissolve (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I in Toluene and Cyclohexane at temperature 70 - 80?;
b.) filter the mixture and wash with hot cyclohexane
c.) Collect ml and cool at 25-35? ;
d.) Stir the mixture for 20-30 min at 25-35?;
e.) Filter reaction mass and wash w/c with Cyclohexane with ketone organic solvent at 25-35?;
f.) Dry reaction mass to obtain pure (R)-5-(1,2-Dithiolan-3-yl) pentanoic acid (a-Lipoic Acid) of formula I.
3.) The process for preparation of alpha lipoic acid claimed in claim 1 and claim 2, wherein organic solvent selected from ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof. In embodiments, the solvent is selected from pentane, hexane, heptane cyclohexane, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate toluene, xylene, ethyl benzene, heptane, hexane, cyclohexane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, carbontetrachloride, 1,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, ethylene chloride, and combinations thereof.
4.) The process for preparation of alpha lipoic acid formula I claimed in claim 1, wherein reducing agents selected from sodium borohydride, lithium aluminium hydride, sodium hydride, hydrazine, diborane.
5.) The process for preparation of alpha lipoic acid formula I claimed in claim 1, wherein phase transfer catalyst is Tetrabutylammonium halides.
6.) The process for preparation of alpha lipoic acid formula I claimed in claim 1, wherein phase transfer catalyst is selected from tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, and methyltri-n-octylammonium chloride.

Dated this 24th Day of March, 2023