Description:FIELD OF INVENTION
The present disclosure relates to a process for the synthesis of R-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 naturally occurring anti-oxidant found in animal and plant tissue. It is known for its numerous and significant biological activities, such as playing a catalytic role in the oxidative decarboxylation of pyruvate to acetate during conversion of glucose to energy and acting as a protein-bound transacylating cofactor for several multi-enzymic alpha-keto acid dehydrogenase complexes. The lipoic acid also plays an important role in phosphorylation, which is vital for the cellular storage and transfer of free energy using energy carrier molecules.
However, the two enantiomeric forms of a lipoic acid do not exhibit the same biological activity. R-a lipoic acid is the (R)-enantiomer of alpha lipoic acid, which is naturally found to be more active. Only the (R)-enantiomer of lipoic acid exists in nature and is responsible for the most beneficial effects of alpha lipoic acid. R- a lipoic acid is essential for aerobic metabolism because it acts as an essential cofactor of many enzyme complexes. The R-a-lipoic acid can be used for treating the co-morbidities caused by diabetes, such as neuropathy, cataract and cardiovascular disease by improving insulin sensitivity in type 2 diabetes. Further, R-a-lipoic acid can delay the aging process, improves brain function and memory, stimulates immune function and supports liver health.
Conventionally known processes for the synthesis of lipoic acid has several disadvantages such as low overall yields, large numbers of steps, poor product quality, a need for separation of diastereoisomers, use of expensive reagents and the like, thereby increasing the production costs. These processes also require highly toxic chemicals which are dangerous during operation and hazardous for the environment.
There is, therefore, felt a need to provide a process for the preparing of R-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 preparing R-alpha lipoic acid.
Another object of the present disclosure is to provide a simple, economical and environment-friendly process for the synthesis of R-alpha lipoic acid.
Still another object of the present disclosure is to provide a process for the synthesis of R- 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 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V). The process comprising reducingan alkyl 8-halo-6-oxooctanoate (Formula I) in the presence of a biocatalyst to obtain an alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II).

The alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II) is sulfonated with a compound of formula III in a fluid medium to obtain a compound of Formula IV.

The compound of (Formula IV) is reacted with a mixture of sodium sulfidenona hydrate and sulfur in at least one alcoholic medium to obtain 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V).

wherein, R1 is selected from H, C1-4 linear or branched chain alkyl; R2 is selected from H, methyl, toluene, p-toluene and X is selected from Cl, Br, I, F.
DETAILED DESCRIPTION OF INVENTION
The present disclosure relates to a process for preparing 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (R-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.
R-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 R-alpha lipoic acid by various routes. However, these methods are associated with drawbacks such as low yield and/ or low purity of R-alpha lipoic acid. Further, these methods require tedious purification steps, thereby resulting in an expensive process. Moreover, the conventional process for synthesis of R-alpha lipoic acid is not industrially feasible.
The present disclosure provides a process for preparing 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V). The process comprising reducingan alkyl 8-halo-6-oxooctanoate (Formula I) in the presence of a biocatalyst to obtain an alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II).

The alkyl (6R)-8-chloro-6-hydroxyoctanoate (Formula II) is sulfonated with a compound of formula III in presence of a first fluid medium to obtain a compound of Formula IV.

The compound of Formula IV is reacted with a mixture of sodium sulfidenona hydrate and sulfur in at least on alcoholic medium to obtain a 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V).
wherein, R1 is selected from H, C1-4 linear or branched chain alkyl; R2 is selected from H, methyl, toluene, p-toluene and X is selected from Cl, Br, I, F.
The process for preparing R alpha lipoic acid is described in detail herein below.
Step (i): Preparation of alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II)
In a first step, an alkyl 8-halo-6-oxooctanoate (Formula I) is reduced in the presence of a biocatalyst to obtain an alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II).

wherein R1 is selected from H, C1-4 linear or branched chain alkyl. In an exemplary embodiment, R1 is methyl.
In accordance with an embodiment of the present disclosure, the biocatalyst is selected from NRBF. In an exemplary embodiment, the biocatalyst is Addzyme 024, Addzyme 026.
In accordance with an embodiment of the present disclosure, the biocatalyst is activated by using a carbohydrate source and a co-enzyme. In an exemplary embodiment, the carbohydrate source is glucose. In an exemplary embodiment, the co-enzyme is NAD+.
In an embodiment of the present disclosure, the compound of Formula 1 is methyl 8-chloro-6-oxooctanoate.
In accordance with the present disclosure, the alkyl 8-halo-6-oxooctanoate (Formula I) is reduced in step (i) at a temperature in the range of 25o C to 30o C.
In accordance with the present disclosure, the alkyl 8-halo-6-oxooctanoate (Formula I) is reduced in step (i) at a pH in the range of 6 to 8.
In accordance with the present disclosure, the alkyl 8-halo-6-oxooctanoate (Formula I) is reduced in step (i) for a time period in the range of 20 to 30 hours.
After the completion of reaction in step (i), the alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II) is extracted in an extraction medium selected from methyl t-butyl ether, followed by complete evaporation of the medium.
In one embodiment, the alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II) is methyl (6R)-8-chloro-6-hydroxyoctanoate
Step (ii): Preparation of alkyl (6R)-8-chloro-6-[(alkylsulfonyl) oxy] octanoate (Formula IV)
In a second step, the alkyl (6R)-8-chloro-6-hydroxyoctanoate (Formula II) is sulfonated with a compound of formula III in a fluid medium to obtain a compound of Formula IV.

wherein, R1 is selected from H, C1-4 linear or branched chain alkyl. In an exemplary embodiment, R1 is methyl.
R2 is selected from H, methyl, toluene, p-toluene. In an exemplary embodiment, R2 is methyl. In another exemplary embodiment, R2 is p-toluene.
X is selected from Cl, Br, I, F. In an exemplary embodiment, X is Cl.
In accordance with an embodiment of the present disclosure, the fluid medium is selected from toluene, trialkylamine C1-4. In an exemplary embodiment, the fluid medium is toluene and trimethylamine.
In accordance with the present disclosure, alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II) is sulfonated in step (ii) for a time period in the range of 1 to 10 hours.
In accordance with an embodiment of the present disclosure, the compound of formula III is a sulphonyl chloride derivative selected from mesyl chloride and p-toluene sulfonyl chloride.
In an embodiment of the present disclosure, the compound of Formula IV is at least one selected from methyl (6R)-8-chloro-6-[(methylsulfonyl) oxy] octanoate and methyl 8-chloro-6-oxooctanoate (6R)-8-chloro-6 [(methyl sulfonyl) oxy] octanoate.
Step (iii): Preparation of 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid / R-(+)- Alpha Lipoic acid
The compound of (Formula IV) is reacted a mixture of sodium sulfidenona hydrate and sulfur in at least on alcoholic medium to obtain 5-[(3R)-1,2-dithiolan-3-yl] pentanoic acid (Formula V).
wherein, R1 is selected from H, C1-4 linear or branched chain alkyl. In an exemplary embodiment, R1 is methyl.
R2 is selected from H, methyl, toluene, p-toluene. In an exemplary embodiment, R2 is methyl. In another exemplary embodiment, R2 is p-toluene.
X is selected from Cl, Br, I, and F. In an exemplary embodiment, X is Cl.
In accordance with an embodiment of the present disclosure, the alcoholic medium is selected from methanol, ethanol and propanol. In an exemplary embodiment, the alcoholic medium is methanol.
In accordance with the present disclosure, the compound of (Formula IV) is reacted with a mixture of sodium sulfidenona hydrate and sulphur in step (iii) at a temperature in the range of 15o C to 25o C. In an exemplary embodiment, the compound of (Formula IV) is added to a mixture of sodium sulfidenona hydrate and sulphur in step (iii) at 20o C.
In accordance with the present disclosure, the compound of Formula IV) is added to a mixture of sodium sulfidenona hydrate and sulphur in step (iii) for a time period in the range of 0.5 to 5 hour under stirring. The stirring is further continued for time period in the range of 5 to 15 hours. In an exemplary embodiment, the compound of (Formula IV) is added to a mixture of sodium sulfidenona hydrate and sulphur in step (iii) for 1.5 hours and the stirring is further continued for 11 hours.
Upon completion of reaction in step (iii) a basic solution is added and stirred for a time period in the range of 2 to 6 hours at a temperature in the range of 20 to 30o C to complete the reaction.
In accordance with an embodiment of the present disclosure, the compound of Formula Vis 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid or R-(+)- Alpha Lipoic acid.
In one embodiment, the compound of Formula Vis 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid is subjected to crystallization in the presence of a mixture consisting of ethyl acetate and cyclohexane to obtain a pure 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid. Typically, the purity of 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid is 99%.
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
Brief Manufacturing Process of 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (R-lipoid acid)

Step I: Preparation of methyl (6R)-8-chloro-6-hydroxyoctanoate
Example 1
Weigh 2.66 gm of KH2PO4 and 5.33 gm of K2HPO4 in 400 ml Deionized water, pH was adjusted to 7.00 with KOH/H3PO4 and make up to 500 ml. D-glucose Anhydrous (120g, 0.66 mole) was dissolved into 400 ml of Phosphate Buffer pH 7.0, after dissolving add the glucose solution to the reaction vessel. In another 4-NRBF charged (2.0 g) of Addzyme-024 and 100 mg of NAD+, dissolved in 100 ml of Phosphate Buffer, and methyl 8-chloro-6-oxooctanoate (100 g, 0.48 mole at 25° C to 30° C. Reaction is maintained at pH 6.95 to 7.00 with 2N NaOH for 24 hrs (± 2). After the completion of reaction, the product was extracted in methyl t-butyl ether, on complete evaporation of solvent gave 75 to 82 g methyl (6R)-8-chloro-6-hydroxyoctanoate as pale-yellow colour product, purity is 88% and SOR +7.05.
Example -2
Weigh 2.66 gm of KH2PO4 and 5.33 gm of K2HPO4 in 400 ml Deionized water, pH was adjusted to 7.00 with KOH/H3PO4 and make up to 500 ml. D-glucose Anhydrous (120g, 0.66 mole) was dissolved into 400 ml of Phosphate Buffer pH 7.0, after dissolving add the glucose solution to the reaction vessel. In another 4-NRBF charged (2.0 g) of Addzyme- 026 and 100 mg of NAD+, dissolved in 100 ml of Phosphate Buffer, and methyl 8-chloro-6-oxooctanoate (100 g, 0.48 mole at 25° C to 30° C. Reaction is maintained at pH 6.95 to 7.00 with 2N NaOH for 24 hrs (± 2). After the completion of reaction, the product was extracted in methyl t-butyl ether, on complete evaporation of solvent gave 86 to 87 g methyl (6R)-8-chloro-6-hydroxyoctanoate as pale-yellow colour product, purity is 88% and SOR +7.05.
Step II:
Example A) Preparation of methyl (6R)-8-chloro-6-[(methylsulfonyl) oxy] octanoate
A solution of methyl (6R)-8-chloro-6-hydroxyoctanoate (10 g 0.047 mole) in 30 ml toluene and (6.30 g 0.62 mole) of triethylamine were stir in 100 ml flask. The mixture was cooled and (6.05 g 0.052 mole) of mesyl chloride were added and stirred the reaction mixture for 5-6 hrs. After removal of the triethylammonium hydrochloride, the solution was concentrated to give 5.4 g methyl (6R)-8-chloro-6-[(methylsulfonyl) oxy] octonoate brown colour oil, purity NLT 85%.
Example B) Preparation of methyl 8-chloro-6-oxooctanoate (6R)-8-chloro-6 [(methyl sulfonyl) oxy] octanoate
A solution of methyl (6R)-8-chloro-6-hydroxyoctanoate (10 g 0.047 mole) in 30 ml toluene and (6.30 g 0.62 mole) of triethylamine were stirred in 100 ml flask. The mixture was cooled and (10.05 g 0.052 mole) of p-toluene sulphonyl chloride were added and stirred the reaction mixture for 10 to 12 hours. After removal of the triethylammonium hydrochloride, the Solution was concentrated to yield 5.4 g methyl (6R)-8-chloro-6-{[(4-methylphenyl) sulfonyl] oxy} octonoate brown colour oil, purity NLT 80%.
Step III: Preparation of 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid / R-(+)- Alpha Lipoic acid
Example A:
A mixture of (1.78 g 0.023 mole) of sodium sulfide Nona hydrate and (0.73 g, 0.023 mole) of sulfur in 48 ml of methanol, to this mixture, a solution of 6.0 g, 0.020 mole) of (methyl (6R)-8-chloro-6-[(methyl sulfonyl) oxy] octanoate in 12 ml methanol was added at 20° C, over a period of 1-2 hours, after which stirring was continued for 10 to 12 hours, on completion of the reaction 15 ml of 10% sodium hydroxide were added and stirred for 4-5 hours at 25° C. After removal of the methanol under vacuum at 35 to 40° C, charge 6 ml water, extracted with 25 ml methyl t-butyl ether at pH 4.50 using acetic acid. After complete distillation of solvent gave crude 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid. Further, 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid on recrystallization in ethyl acetate: cyclohexane mixture gives 2.1 g pure 5-[(3R)-1,2-dithiolan-3-yl] pentanoic acid, Purity by HPLC 99.00%, cc NLT 99.0%, SOR-+102
Example B:
A mixture of (2.41 g 0.019 mole) of sodium sulfide Nona hydrate and (0.58 g, 0.018 mole) of sulfur in 48 ml of methanol, to this mixture, a solution of 6.0 g, 0.017 mole) of methyl (6R)-8-chloro-6-{[(4-methylphenyl)sulfonyl]oxy} octanoate in 12 ml methanol was added at 20° C, over a period of 1-2 hours, after which stirring was continued for 10-12 hours, on completion of reaction 15 ml of 10% sodium hydroxide were added and stirred for 4-5 hours at 25° C. After removal of the methanol under vacuum at 35-40° C, charged 6 ml water, and extracted with 25 ml methyl t-butyl ether at pH 4.50 using acetic acid. After complete distillation of solvent gave crude 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid. Further, 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid on recrystallization in ethyl acetate: cyclohexane mixture gave 2.1 g pure 5-[(3R)-1,2-dithiolan-3-yl] pentanoic acid, Purity 99.00%, SOR-+101.

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 R-lipoic acid, which:
- is feasible for large scale manufacturing;
- is simple, economical and environment-friendly; and
- provides high yield and high purity.
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 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V), said process comprising the following steps:
i. reducingan alkyl 8-halo-6-oxooctanoate (Formula I) in the presence of a biocatalyst to obtain an alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II);

ii. sulfonating said alkyl (6R)-8-halo-6-hydroxyoctanoate (Formula II) with a compound of formula III in a fluid medium to obtain a compound of Formula IV; and

iii. reacting said compound of (Formula IV) with a mixture of sodium sulfidenona hydrate and sulfur in at least one alcoholic medium to obtain 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid (Formula V).

wherein, R1 is selected from H, C1-4 linear or branched chain alkyl;
R2 is selected from H, methyl, toluene, p-toluene and
X is selected form Cl, Br, I, F.
2. The process as claimed in claim 1, further comprising crystallizing said compound of Formula V in a mixture consisting of ethyl acetate and cyclohexane to obtain a pure 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid.
3. The process as claimed in claim 1, wherein said biocatalyst is selected from the group consisting of NRBF, Addzyme 024, Addzyme 026 and co-enzyme.
4. The process as claimed in claim 1, wherein said fluid medium is selected from toluene, trialkyl amine and triethyl amine.
5. The process as claimed in claim 1, wherein said alcoholic medium is selected from methanol, ethanol and propanol.
6. The process as claimed in claim 1, said compound of Formula 1 is methyl 8-chloro-6-oxooctanoate.
7. The process as claimed in claim 1, said compound of Formula II is methyl (6R)-8-chloro-6-hydroxyoctanoate.
8. The process as claimed in claim 1, wherein said formula III is a sulphonyl chloride derivative selected from mesyl chloride and p-toluene sulfonyl chloride.
9. The process as claimed in claim 1, said compound of Formula IV is at least one selected from methyl (6R)-8-chloro-6-[(methylsulfonyl) oxy] octanoate and methyl 8-chloro-6-oxooctanoate (6R)-8-chloro-6 [(methyl sulfonyl) oxy] octanoate.
10. The process as claimed in claim 1, said compound of Formula V is 5-[(3R)-1, 2-dithiolan-3-yl] pentanoic acid or R-(+)- Alpha Lipoic acid.