A green enantioselective synthesis of sulfoxide compounds

Abstract

The invention disclosed herein relates to metal-catalyst free, green enantioselective synthesis of sulfoxide compounds of Formula-I. Particularly, the present invention relates to in situ process to obtain enantioselective sulfoxide compounds of Formula-I with high yield and purity and specific optical rotation. Further, the enantioselective sulfoxide compounds of Formula-I are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorder.

Description

[0001] A GREEN ENANTIOSELECTIVE SYNTHESIS OF SULFOXIDE COMPOUNDS

[0002] TECHNICAL FIELD:

[0003] The present invention relates to metal-catalyst free, green enantioselective synthesis of sulfoxide compounds of Formula-I. Particularly, the present invention relates to in situ process to obtain enantioselective sulfoxide compounds of Formula-I with high yield and purity and specific optical rotation. Further, the enantioselective sulfoxide compounds of Formula-I are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorders.

[0004] BACKGROUND:

[0005] Green synthesis is an environment friendly method delivering diverse ways of thinking in chemistry intended to eliminate toxic, harmful waste, reduce energy consumption, and to use ecological solvents. Green synthesis is required to avoid the production of unwanted or harmful by-products through the build-up of reliable, sustainable, and eco-friendly synthesis procedures.

[0006] In the past years, extraordinary progress has been made in continuous enantiomeric separation, implementing more efficient procedures, and contributing to developing greener and more sustainable separation processes.

[0007] Chiral heteroorganic compounds, particularly those containing sulphur or phosphorus, continue to receive extreme interest of researchers due to their applicability in organic synthesis and interesting biological activities. Enantioselective approach caused an explosion of its application in organic synthesis and particularly in the preparation of chiral nonracemic products.

[0008] Chiral structures profoundly influence chemical and biological processes. While chiral carbon biomolecules have received much attention, chirality is also possible in certain sulphur compounds like esomeprazole, a chiral sulfoxide, is used for its superior clinical properties as a proton pump inhibitor over the racemic mixture, omeprazole.

[0009] Sulfoxide, is an organosulfur compound containing a sulfinyl (>SO) functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are oxidized derivatives of sulfides.

[0010] Over the last few decades, more than 40 different classes of chiral sulphur compounds have been described in the various chemical literatures and a large number of useful procedures for the synthesis of enantiomerically pure sulphur compounds have been developed. Chiral sulfoxides are important for the synthesis of flavours and fragrances, chiral precursor molecules, active pharmaceutical ingredients and as auxiliaries in chemical synthesis. Chiral sulfoxides are important intermediates in asymmetric synthesis and as bioactive ingredients in the pharmaceutical industry. A recent industrial application of the enantioselective oxidations of sulfides using chiral metal catalysts was the development of nonsteroidal anti-inflammatory drug (NSAID). Particularly, synthesis was based on an iron- catalysed sulfoxidation or titanium-mandelic acid complex [H. Pellissier / Tetrahedron 62 (2006) 5559 5601].

[0011] W02001021617A1 discloses a process of preparing a sulfoxide compound comprises reacting a sulfide compound with hydrogen peroxide in an ethanol solvent in the presence of a rhenium catalyst.

[0012] US9932305B2 relates to a process for the asymmetric oxidation of nucleophilic organic compounds, particularly metal-free, with peroxide compounds in the presence of a chiral imidodiphosphate catalyst.

[0013] EP1334956A2 provides a method for preparing a sulfone or sulfoxide compound, characterized in that a sulfide compound is allowed to react with hydrogen peroxide in the presence of a metal oxide catalyst wherein metal compound selected from tungsten metal, molybdenum metal.

[0014] Further, it is reported that oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide or niobium carbide provides the corresponding sulfoxides in high yields. Both catalysts can easily be recovered and reused without losing their activity [M. Kirihara, A. Itou, T. Noguchi, J. Yamamoto, Synlett, 2010, 1557-1561].

[0015] The oxidation of sulfanes to sulfoxides without any overoxidation to sulfones using a combination of hydrogen peroxide and triflic acid disclosed in Synthesis, 2008, 1682-1684.

[0016] Further, S. S. Kim, et.alJung, Synthesis, 2002, 2484-2486 reports selective oxidation of sulfides to sulfoxides with periodic acid (HsIOe) catalyzed by FeCh in acetonitrile.

[0017] Most of the existing oxidation methods involve transition metal catalyst or enzyme catalyst However, the main limitation of using enzymatic catalyst in commercial scale is the high cost of lipase and slow reaction rate.

[0018] On the other side, metal-catalyzed like mercury systems usually suffer from some limitations like metal contamination, over-oxidation, a limited substrate scope etc. In contrast to the significant progress in metal catalysis, the organocatalytic methods are still under development, although organocatalysis has experienced an explosive progress and expansion during the last decade.

[0019] There are few metal-free methods achieved by using chiral imines or oxaziridiniums for high enantio selectivity, but these transformations require stoichiometric amounts of the chiral reagents and the corresponding catalytic systems are relatively less efficient. Considering the importance of optically pure sulfoxides in synthetic and medicinal chemistry, a general, metal-free, and highly enantioselective green sulfoxidation reaction of sulfides is highly desirable.

[0020] One significant problem associated with chiral sulfoxide compound is its inherent instability. The compounds are unstable in liquid form which rapidly degrades under normal conditions. This makes exceptionally hard to manufacture biologically active form of sulfoxide compounds.

[0021] Therefore, there is also a need for simple process to obtain enantioselective sulfoxide compounds with high yield and purity and substantial stability.

[0022] Thus, the present inventors have developed a novel and metal-free method for the enantioselective oxidation of sulfides, a viable approach for oxidation of sulfide and induction of chirality to the end product by using chiral aprotic acid without multiple separation.

[0023] OBJECTIVE:

[0024] The objective of the present invention relates to green enantioselective synthesis of sulfoxide compounds of Formula-I.

[0025] Another objective of the present invention is to provide green synthesis for enantioselective sulfoxide compounds of Formula I by employing chiral aprotic agent or acid.

[0026] Yet another objective of present invention is to provide industrially viable in situ process for the preparation of chiral sulfoxide compounds of the Formula I with higher purity, yield and specific optical rotation and enantiomeric excess of R isomer.

[0027] Another objective of the invention is to provide effective composition of sulfoxide compounds of formula I for the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorders. SUMMARY:

[0028] To meet the above objectives, the inventors of the present invention carried out thorough experiments to establish effective, viable green process for preparation of optically active organosulfur compound for treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorder.

[0029] In a particular aspect, the present invention relates to metal-catalyst free green enantioselective synthesis of sulfoxide compounds of Formula-I.

[0030] In another aspect, the invention relates to in situ process for synthesis of compounds of formula-I comprising steps of formation of isothiocyanates followed by chiral oxidation to obtain enantioselective sulfoxide compounds of Formula-I with high yield and purity and specific rotation.

[0031] Formula-I wherein n is integer ranging from 1 to 6.

[0032] In another aspect, the present invention relates to metal-catalyst free, green enantioselective synthesis of sulfoxide compounds of Formula-I with enantiomeric excess of (R) isomer.

[0033] In yet another aspect, the present invention relates to green enantioselective synthesis of sulfoxide compounds of Formula-I by employing chiral aprotic resolving agent and green solvents. In further aspect, the process of the present invention avoids lengthy steps, avoid use of large amounts of solvents and expensive metal catalysts thereby avoiding yield loss and making process substantially simple, safe and cost-effective.

[0034] Further, the enantiomeric excess of (R) isomer is readily amenable to subsequent processing steps to provide a more stable form of the compounds of Formula -I

[0035] In another aspect, the enantioselective sulfoxide compounds of Formula-I are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorder.

[0036] BRIEF DESCRIPTION OF FIGURES:

[0037] Figure 1 illustrates the chiral HPLC chromatogram of (R) isomer of Compound of Formula I (R)-l-isothiocyanato-4-[methlysulfmyl] butane.

[0038] DETAILED DESCRIPTION:

[0039] The invention will now be described in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

[0040] It is further to be understood that all terminology used herein is for the purpose of describing particular embodiment only and is not intended to be limiting in any manner or scope. Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain.

[0041] In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.

[0042] As used in the specification the singular forms "a" "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of solvents, reference to "an agent" includes mixtures of two or more such agents, and the like.

[0043] The term “pharmaceutically / nutraceutically acceptable salt,” as used herein, represents those salts which are within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Particularly, the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, alkali or alkaline earth metal salts, as well as solvates, cocrystals, polymorphs and the like of the salts.

[0044] All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the transitional phrase “comprising” allows the inclusion of other elements to be within the scope of the invention.

[0045] The term ‘enantioselective’ refers to a process or reaction that selectively produces one enantiomer (a specific mirror-image form of a molecule) over the other.

[0046] The optical purity is equal to the percentage excess of the major enantiomer over the minor enantiomer. This term, the “enantiomeric excess”, or “e.e.” is equivalent to the optical purity or expressing the enantiomeric purity of a mixture.

[0047] The process involved in the present invention comprising readily available, readily biodegradable, readily recyclable green solvents, where the intermediates and feedstocks have acceptable and appropriate toxicity and ecotoxicity.

[0048] In a preferred embodiment, the present invention relates to metal-catalyst free, green enantioselective synthesis of sulfoxide compounds of Formula-I.

[0049] Formula-I n= 1 to 6

[0050] In another embodiment, the invention relates to in situ process for synthesis of compounds of formula-I comprising steps of formation of isothiocyanates followed by chiral oxidation with chiral aprotic sulfonic acid to obtain enantioselective sulfoxide compounds of Formula-I with high yield, purity with specific optical rotation.

[0051] In another embodiment, the invention provides enantioselective sulfoxide compounds of Formula-I which are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorder.

[0052] In another embodiment, the invention provides cost-effective, green enantioselective synthesis of sulfoxide compounds of Formula (I) with high purity and good yield.

[0053] In yet another embodiment, the present invention provides green enantioselective synthesis of sulfoxide compounds of Formula (I) with high purity and good yield.

[0054] Formula (I) wherein n is 1 to 6.

[0055] In one preferred embodiment, the present invention provides green enantioselective synthesis sulfoxide compounds of Formula (I)

[0056] Formula (I) wherein the steps involve; a. in situ formation of isothiocyanate;

[0057] Formula-II b. Chiral oxidation of compounds of Formula (II) tion

[0058] Formula-I wherein n is integer ranging from 1 to 6.

[0059] In some embodiment, the present invention provides in situ process for the synthesis of optically active R isomer of sulfoxide compounds comprising formation of isothiocyanates compounds of formula II followed by selective chiral oxidation. Particularly, the formation of isothiocyanates compounds of formula II is promoted by the low-cost and readily available base from primary amines of formula III and carbon disulfide in a one-pot procedure. The developed protocol features no extra desulfurizing reagents under mild conditions. The formation and decomposition of the dithiocarbamate intermediate is done rapidly to form desired isothiocyanates with high purity and yield.

[0060] In some embodiment, the present invention provides in situ process for the formation of isothiocyanates comprising following steps Formation of dithiocarbamate: The primary amine of formula III reacts with carbon disulfide (CS2) in the presence of a base triethylamine, (EtsN) to form a dithiocarbamate; Oxidation with hydrogen peroxide (H2O2): The dithiocarbamate intermediates then reacts with hydrogen peroxide (H2O2) in the presence of a polar aprotic solvent such as tetrahydrofuran (THF), acetone, ethyl acetate. This step oxidizes the dithiocarbamate to form the desired isothiocyanate of Formula II; NaCl Addition: sodium chloride (NaCl) is added to the reaction mixture to facilitate phase separation and purification of the isothiocyanate product.

[0061] In another embodiment, the chiral oxidation of isothiocyanate compounds of Formula (II) to form chiral sulfoxide compounds of Formula (I) is carried out in presence of chiral aprotic acid. The chiral aprotic acid is an organosulfur compound typically chiral sulfonic acid.

[0062] In another embodiment, the chiral sulfonic acid is 10-Camphorsulfonic acid (CSA) which is used as a resolving agent or chiral auxiliary, as well as oxidising agent. The acid is soluble in water, ethanol, and ether, and has ability to form highly stable enantioselective sulfoxide compounds.

[0063] Further, CSA can induce chirality or enhance the existing chirality in molecules, particularly in carbonyl, sulfonyl compounds. In practical terms, the use of CSA in preparing the R isomer involves techniques like crystallization, recrystallization, or precipitation from a solution, where the conditions are adjusted to favour the R enantiomer over the S enantiomer or the racemic mixture.

[0064] Overall, CSA is valued for its ability to selectively interact with chiral molecules and facilitate the separation or preparation of optically active compounds.

[0065] The chiral camphor sulfonic acid (CSA) is used in the molar ratio of 1 : 1 or 1:2 with respective to isothiocyanates compound of Formula II. Preferably CSA is used in 1 to 2 equivalent weights.

[0066] In another embodiment, the process further provides inclusion complex of enantiomerically pure R isomer with suitable complexing agent.

[0067] The suitable complexing agents are cyclodextrins such as a-Cyclodextrin, P- Cyclodextrin, y-Cyclodextrin, and their derivatives (e.g., hydroxypropyl-P-cyclodextrin), Ethylenediaminetetraacetic Acid (EDTA) such as Disodium EDTA, calcium disodium EDTA, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), amino acids such as arginine, lysine, glycine, phosphatidylcholine, phosphatidyl serine, preferably complexing agent is a-Cyclodextrin has higher affinity to form inclusion complex with R enantiomer.

[0068] The complexing agent is used in the weight ratio of 1 :0.5 to 1 : 10 with respect to the optically pure R isomer of sulfoxide compounds.

[0069] In yet another embodiment the enantioselective sulfoxide compounds of Formula I where (R) enantiomer of a chiral product is preferentially produced with enantiomeric excess more than 95%.

[0070] In some embodiment, the process of the present invention is efficient and provides high yields of the desired end product of Formula I without significant production of the byproducts.

[0071] In some embodiment, the present invention provides enantioselective sulfoxide compounds of Formula-I which are useful in the treatment of neurological, neuropsychiatric, metabolic and neurodevelopmental disorder. Preferably in the treatment of autism, cancer, diabetes, microbial / viral infections, obesity, chronic inflammation of the respiratory, hepatic, gastrointestinal, renal, cutaneous or ophthalmic systems, muscular atrophy, oxidative stress, hay fever, autism, asthma, liver disease, sunburn, high blood pressure, schizophrenia. In some embodiment, the present invention provides a method for treating neurodevel opmental disorders in a subject in need thereof. The method comprises administering of a therapeutically effective amount of a medicinal composition comprising chiral sulfoxide compounds of Formula-I along with pharmaceutically acceptable excipients.

[0072] In some embodiment, the present invention provides technically advanced, in situ process for the preparation of chiral sulfoxide compounds of Formula (I) by forming isothiocyanate compounds of Formula (II) from sulfur containing primary amine compounds of Formula (III) followed by selective chiral oxidation compound of a Formula (II) in presence of chiral agent and green solvents.

[0073] In some embodiment, the green solvents used in the in situ reaction are selected from water, acetone, ethanol, 1 -propanol, isopropanol, toluene, ethyl acetate, methanol, t-butanol, 1- butanol or mixtures thereof.

[0074] In another embodiment, the temperature maintains for rearrangement reaction, where primary amine reacts with carbon disulfide below 0 °C. Carbon disulphide is added drop wise in order to keep the temperature of the reaction mixture low. The reaction mixture warmed between 5°C and 30°C, more preferably to between 5°C and 20 °C and then the oxidizing agent hydrogen peroxide is added in presence of polar aprotic solvent THF.

[0075] In another embodiment, the primary amine compounds of Formula III are selected from the group consisting of 2-(methylsulfanyl)ethan-l-amine,3-(methylsulfanyl)propan-l- amine,4-(methylsulfanyl)butan-l -amine, 5-(methylsulfanyl)pentan-l-amine.

[0076] In yet another embodiment, the isothiocyanates compounds of Formula II are selected from the group consisting of l-isothiocyanato-2-(methylsulfanyl)ethane; l-isothiocyanato-3- (methylsulfanyl)propane; 1 -isothiocyanato-4-(methylsulfanyl)butane; 1 -isothiocyanato-5- (methylsulfanyl)pentane.

[0077] In another embodiment, the presently improved in situ process provides compounds of Formula II with high purity and yield, wherein the yield and purity is not less than 80% after drying.

[0078] In yet another embodiment, the chiral sulfoxide compounds of Formula I is selected from the group consisting of l-isothiocyanato-2-[(R)-methanesulfinyl]ethane; 1- isothiocyanato-3-[(R)-methanesulfinyl]propane; l-isothiocyanato-4-[(R)-methanesulfmyl] butane; l-isothiocyanato-5-[(R)-methanesulfmyl]pentane. In another embodiment, the presently improved in situ process provides compounds of Formula- I with high purity and yield, wherein the yield and purity is not less than 80%. Preferably, the practical yield is in the range of 80% to 100%, where purity is in the range of 90 % to 99%.

[0079] In another embodiment the specific optical rotation of R isomer of sulfoxide compounds of Formula- 1 is -76°C±3 , laevorotation.

[0080] In another embodiment the enantiomeric excess of R isomer of sulfoxide compounds of Formula- 1 in the racemic mixture is in the range of 90-99%.

[0081] In another embodiment the examples of suitable reagents and solvents are selected from water, acetic acid, acetone, acetylene, DMF, DMSO, methanol, ethanol, propanol, butanol, acetonitrile, diethyl ether, ethyl acetate, carbon tetrachloride, methylene chloride, chloromethane, ammonia, chloromethane, sodium methyl mercaptan, sodium ethyl mercaptan, sodium methoxide sodium ethoxide, ammonium hydroxide, hexane, butanone (methyl ethyl ketone), butylated hydroxytoluene, n-butyllithium, carbon disulfide, carbon tetrachloride, chloroform, chromic acid, diethyl ether, dihydropyran, diisobutylaluminium hydride, dimethyl ether, dimethylformamide, dimethylsulfide, dimethyl sulfoxide, dioxane, ethanol, formaldenyde, formic acid, Grignard reagents, , hydrazine, hydrazoic acid, hydrochloric acid, hydrofluoric acid, hydrogen peroxide, imidazole, isopropyl alcohol, lime, limestone, lithium aluminium hydride, manganese dioxide, methyl tert-butyl ether, methyl mercaptan sodium nitric acid, perchloric acid, phosphoric acid, phosphoryl chloride, potassium dichromate, potassium hydroxide, sodium borohydride, sodium chlorite, sodium hydride, sodium hydroxide, sodium hypochlorite, sodium methanethiolate, sodium mercaptides, sodium nitrite, sulfuric acid, tert-butyl hydroperoxide, tetramethylammonium hydroxide, tetramethylsilane, thionyl chloride, thiophenol and etc. in combination thereof.

[0082] In certain embodiments, the chiral sulfoxide compounds of formula I are enriched with R isomer, the enantiomeric excess is preferably R isomer in the mixture. The optically active R isomer of sulfoxide compounds of formula I is further stabilized with the formation of inclusion complex.

[0083] In one another embodiment, the invention provides green enantioselective synthesis of (R)-l-isothiocyanato-4-[methlysulfmyl] butane from 4-(m ethyl sulfanyl) butan-1 -amine comprising steps of; formation of l-isothiocyanato-4-(methylsulfanyl)butane from 4- (methyl sulfanyl) butan-1 -amine followed by chiral oxidation of l-isothiocyanato-4- (methyl sulfanyl)butane to form optically active(R)-l-isothiocyanato-4-[methlysulfmyl] butane.

[0084] 4-(m ethyl sulfanyl) butan-1 -amine 1 -isothiocyanato-4-

[0085] (methyl sulfanyl)butane

[0086] In another embodiment, (R)-l-isothiocyanato-4-[methlysulfinyl] butane is further stabilized with complexing agent such as a- cyclodextrin or biodegradable chelating agent / chelator(s) such as GLDA (L-glutamic acid N, N-diacetic acid), MGDA (methylglycinediacetic acid), EDDS (ethylenediamine-N,N'-disuccinic acid), ASDA (L-aspartic acid N, N-diacetic acid), Sodium Gluconate, NTA (nitrilotriacetic acid), and IDS (iminodisuccinic acid) in presence of green solvent.

[0087] In another embodiment, the specific optical rotation of (R)-l-isothiocyanato-4- [methlysulfinyl] butane is -76°C , laevorotation.

[0088] In another embodiment, the enantiomeric excess of (R)-l-isothiocyanato-4- [methlysulfinyl] butane is in the range of 95-99%, preferably 98%.

[0089] In yet another embodiment, the present invention provides compounds of Formula-I, a potent organosulfur compound useful in the preparation of medicament for treatment of certain neuropsychiatric disorders, neurological disorders, metabolic disorders, neurocognition disorder, neurodevel opmental disorders.

[0090] Generally, neuropsychiatric disorders include but are not limited to schizophrenia, schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, schizotypal personality disorder, major depressive disorder, bipolar disorder, chronic hallucinatory psychosis, dissociative disorders, obsessive compulsive disorder, induced delusional disorder, posttraumatic stress disorder, menstrual psychosis, cycloid psychosis depression, mania (Bipolar disorder), visual hallucination, auditory hallucination, eating disorder, attention deficit hyperactivity disorder, Tourette's syndrome, other movement disorders, substance dependence (alcohol, cocaine), bipolar affective disorders, or unipolar affective disorder, adolescent conduct disorder.

[0091] Further, the term ‘neurological disorders’ relates to any disorder of the nervous system (central and peripheral nervous system), structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves like cranial nerves, peripheral nerves, nerve roots, autism (ASD), autonomic nervous system, neuromuscular junction, and muscles that can result in a range of symptoms. These disorders include epilepsy, Alzheimer’s disease, dementia, cerebrovascular diseases including stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfectious, brain tumours, traumatic disorders of the nervous system due to head trauma.

[0092] Further, the term neurocognition disorder, defined as a significant decline in cognitive abilities that is severe enough to interfere with the individual’s everyday activities, dementia, ADHD, memory loss, Alzheimer, Lewy body disease, HIV, Huntington disease, Parkinson disease, Lewy body disease, Creutzfeldt-Jakob disease, Traumatic brain injury, Frontotemporal Degeneration, Multiple sclerosis, Normal pressure hydrocephalus.

[0093] Additionally, the term metabolic disorder refers to any disorder which occurs when abnormal chemical reactions in human body disrupt the metabolic processes. Metabolic syndrome is a cluster of conditions that occur together, increasing risk of heart disease, cardiovascular disorders, atherosclerosis, arteriosclerosis, stroke, ischemic stroke, brain stroke, brain haemorrhage type 2 diabetes, dyslipidaemia high blood pressure, high blood sugar, abdominal obesity, liver health, NASH, ASH and abnormal cholesterol or triglyceride levels.

[0094] In some embodiment, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, are formulated for medicaments, which preferably take the form of therapeutically effective individual doses adjusted to the form of administration.

[0095] In some embodiment, the daily dose of a pharmaceutical composition comprising sulfoxide compounds of Formula I disclosed herein varies over a wide range from about 0.1 mg to about 5000 mg; preferably, the dose is in the range of about 1 mg to about 1000 mg per day for an average human.

[0096] The term "therapeutically effective amount " denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and / or reduction or restoration or modulation, regulation of at least one indicator / biomarker (e.g., blood or serum CRP level), and / or minimize at least one clinical symptom related to neurological disorders like ASD.

[0097] A "therapeutically effective amount" means the amount of the compound that, when administered to a subject to treat a disease or condition referred to herein, is sufficient to perform such treatment for the disease or condition.

[0098] The "therapeutically effective amount" will vary depending on the form of the compound (for example, the form of the salt), the disease or condition in question and its severity, as well as the age, weight, etc., of the subject to be treated.

[0099] The term ‘subject in need thereof’ pertains to a subject preferably mammal, more preferably a human suffering or suspected with neuropsychiatric disorder.

[0100] In the context of the present invention, the term “treatment” refers to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, down regulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, modulate, prevent, inhibit, stabilize, ameliorate, cure, heal, maintain, normalize, optimize neurological disorders observed in the subject in need thereof.

[0101] Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the invention are formulated in geometric or, enantiomeric or stereoisomeric forms.

[0102] In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the invention. Compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates of a compound intends the inclusive meaning of “or”, in those materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed. Some of the crystalline forms of the compound exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

[0103] In some embodiment, the invention provides medicinal compositions comprising sulfoxide compounds of Formula I present in effective amount along with pharmaceutically acceptable excipients. As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients also include, for example: anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

[0104] In another embodiment, the present invention provides compounds of Formula I useful in the preparation of the medicinal composition comprising chiral sulfoxide compounds which can be prepared in a manner well known in the pharmaceutical art and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0105] The preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal or oral.

[0106] In some embodiment, the present invention provides sulfoxide compounds of Formula I useful in the preparation of the solid pharmaceutical or medicinal composition comprising fine particles or crystalline form of compounds of chiral R-sulfoxide.

[0107] In some embodiment, the present invention provides compounds of Formula I useful in the preparation of medicinal composition comprising R isomer of sulfoxide compounds administered to a subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, water in oil or oil in water emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film, spray.

[0108] In another embodiment, the composition is formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, intracerebral, intracerebroventricular, or intradermal routes of administration.

[0109] In a further embodiment, the present composition is formulated in the form of age- appropriate paediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films, orodispersible tablets.

[0110] Further, the present composition can be formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films orodispersible tablets. It can also be prepared in the form of known food products.

[0111] Notably, the present composition is stable, non-hazardous, non-toxic and safe for human consumption without any side effects, therefore the present nutritional composition can also be used under preventive therapy / adjuvant therapy / add-on therapy / combination therapy in a subject in need thereof.

[0112] In another embodiment, the compounds of Formula I of the present invention and end products thereof are non-toxic, cost effective, enriched with nutrients or biomolecules and provides safeguard against problems associated with neurodevelopment without any adverse effect.

[0113] In some embodiments, the compounds of Formula-I are useful for the formulation of chiral R sulfoxide medicaments by using pharmaceutically acceptable excipients such as diluents, binders, lubricants, solubilizing agents, surfactants, stabilizers, colors, flavoring agents, sweeteners, glidants, plasticizers, and other additives.

[0114] In yet another embodiment, the invention provides a medicinal composition comprising compounds of Formula I along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.

[0115] In another embodiment, the present invention provides a method for treating neuropsychiatric disorders in a subject in need thereof. The method comprises administering an oral dose of a therapeutically effective amount of a medicinal composition comprising compounds of Formula-I along with pharmaceutically acceptable excipients. In certain embodiments, the invention provides the potent synergistic medicinal composition wherein the effective unit dose for an oral administration is formulated in a range of 1 to 1000 mg.

[0116] It is further recommended that children, patients over 60 years old, initially receive low doses and that the dosage be titrated based on individual physiological responses and / or pharmacokinetics. It can be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. The present composition can be used as infant formula as well as adult formula by varying the concentration of active ingredients. Further, it is noted that the dietician or nutritionist or certified physician knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.

[0117] The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0118] While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

[0119] The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention.

[0120] The invention may be further be illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

[0121] The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims and examples, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

[0122] EXAMPLES:

[0123] Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention. Example-1: Green - insitu synthesis of chiral sulfoxide compounds of Formula -I

[0124] Formula III Formula-II

[0125] (Sulfur containg (Isothiocynate compounds) primary amine compounds ) Chiral oxidation 1 CSA]

[0126] Formula (I)

[0127] (Chiral sulfoxide compounds)

[0128] Table -1: Compounds of formula-III

[0129] Table -2: Compounds of formula-II Table -3: Compounds of formula-I

[0130] Example 2: synthesis of l-isothiocyanato-4-(m ethyl sulfanyl) butane from 4-(m ethyl sulfanyl) butan-1 -amine

[0131] 4-(methylsulfanyl) butan-l-amine l-isothiocyanato-4-(methylsulfanyl)butane

[0132] In a multi-neck round bottom flask, 4-(m ethyl sulfanyl) butan-l-amine (1.0 equiv.) and triethylamine (1.0 equiv.) were added, and the solution was further stirred until it had cooled below -10° C in presence of 10 volume of THF. Carbon disulfide (1.0 equiv.) was added dropwise over 2 hours while keeping the internal temperature below -3° C and later warmed to 10° C. Hydrogen peroxide (35% aq, 1.0 equiv.) was added slowly while keeping the internal temperature below 20° C. (bath temperature was 0° C ), further on extraction with ethyl acetate followed by treatment with 10% sodium chloride solution and activated charcoal. The reaction mass was filtered and washed with organic solvent to obtain yellowish (l-isothiocyanato-4- (methyl sulfanyl) butane (85% yield) with 95% purity.

[0133] Example 3: Synthesis of (R)-l-isothiocyanato-4-[methlysulfinyl] butane OR 1-isothiocyanato-

[0134] 4-[(R)-methanesulfinyl] butane from l-isothiocyanato-4-[methylsulfanyl] butane

[0135] In multi-neck round bottom flask 10-camphorsulfonic acid (20 mmol, 2 equiv.) and (1- isothiocyanato-4-[methylsulfanyl] butane (10 mmol, 1 equiv.) were taken in ethyl acetate (100 mL) and the contents were stirred at 25°C for 24 h and filtered. The precipitate was suspended in a mixture of ethyl acetate and aq. NazCOs (2M) and stirred until dissolution occurred. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic extract was washed with brine. To this reaction mixture hydrogen peroxide (35% aq, 1.0 equiv.) was added slowly while maintaining temperature between -10°C. (bath temperature was 0° C ), further on extraction with ethyl acetate followed by treatment with 10% sodium chloride solution and activated charcoal. The reaction mass was filtered and washed with organic solvent to obtain yellowish (R)-l-isothiocyanato-4-[methlysulfinyl] butane (90% yield) with 97% purity, ee % purity 98%.

[0136] Molecular Weight, 177.288. Molecular formula: C6H11NOS2; Density, 1.2±0.1 g / cm3 ; Boiling Point, 370.52°C at 760 mmHg ;

[0137] 'H NMR (in DMSO-d6) (S-CH3): 52.58 ppm (s, 3H); (S-CH2): 52.95 ppm (t, J = 6.8 Hz, 2H); (CH2-CH2): 5 1.73-1.82 ppm (m, 4H)

[0138] 13C NMR (in DMSO-d6) (S-CH3): 5 39.2 ppm; (S-CH2): 5 28.3 ppm; (CH2-CH2): 5 25.8 ppm and 5 29.5 ppm; (N=C=S): 5 133.2 ppm; (S=O): 5 61.7 ppm i) Specific Optical Rotation Process for (R)-l-isothiocyanato-4-[methly sulfinyl] butane

[0139] (R)-l-isothiocyanato-4-[methlysulfinyl] butane (1 equiv.) was weighed in a 1 mL volumetric flask and dissolved in chloroform (concentration (c) expressed in g / 100 mL). The solution was transferred into a 1 mL cell (path length 1 dm) and the optical rotation [a]n was measured at 25CC on a polarimeter.

[0140] The observed specific optical rotation (fa]_(obs) of the mixture: -76°

[0141] The specific optical rotation (fa]_pure) of the pure enantiomer: -80°

[0142] Enantiomeric excess (ee) is a measure of the purity of a mixture of enantiomers, representing the excess of one enantiomer over the other. % enantiomeric exess 100

[0143] =95%

[0144] The enantiomeric excess (ee) of R-sulforaphane= 98% ii) Chiral Chromatography Process for (R)-l-isothiocyanato-4-[methlysulfmyl] butane

[0145] Column: Chiralpak AD-H (250 mm x 4.6 mm, 5 pm); Mobile Phase: Hexane: Methanol (80:20, v / v); Flow Rate: 1.0 mL / min; Temperature: 25°C; Injection Volume: 10 pL; Detection: UV at 254 nm

[0146] The prepared sample solution was injected with the concentration (1 mg / mL) followed by further dilution of 0.1 mg / mL (100 pg / mL), pipette 1 mL of the 1 mg / mL stock solution into a 10 mL volumetric flask and dilute to the mark with the mobile phase. The chromatogram was monitored and recorded the retention times of the R enantiomer. The retention times and peak areas were compared to identify and quantify the enantiomers of (R)-l-isothiocyanato-4- [methlysulfinyl] butane. By measuring the retention times or peak areas of the chromatographic peaks, the enantiomeric excess (ee) or the ratio of R and S enantiomers in the mixture was calculated.

[0147] HPLC ASSAY - R isomer purity 97%

[0148] The enantiomeric excess (ee) of R-sulforaphane =98%

[0149] Example 4: Inclusion Complex of (R)-l-isothiocyanato-4-[methlysulfinyl] butane with Cyclodextrin

[0150] The (R)-l-isothiocyanato-4-[methlysulfinyl] butane (1 equv.) yellowish solution was treated with a- Cyclodextrin (3 equiv.) in presence of ethyl acetate at temperature below 20°C. The reaction mixture was cooled down using ice-methanol bath and stirred for 3 to 4 hr at that temperature. The precipitated white solid was filtered and dried under high vacuum at room temperature (75% yield) with 95% purity.

[0151] Example 5: Inclusion Complex of (R)-l-isothiocyanato-4-[methlysulfmyl] butane with EDTA (R)-l-isothiocyanato-4-[methlysulfinyl] butane is quite unstable, especially in aqueous solutions, so the process should be carried out under conditions that minimize degradation (e.g., low light, low temperature).

[0152] Formation of an inclusion complex of (R)-l-isothiocyanato-4-[methly sulfinyl] butane with EDTA involves complexation chemistry where EDTA (ethylenediaminetetraacetic acid) can form a stable complex with (R)-l-isothiocyanato-4-[methlysulfinyl] butane, potentially enhancing its stability and solubility.

[0153] 0.1 moles of EDTA was dissolved in 500 mL of distilled water. Further 0.1 moles (1 equv) of (R)-l-isothiocyanato-4-[methlysulfinyl] butane in 100 mL of ethanol. The two solutions combined while stirring, and adjusted the pH to 7.5 using NaOH or HC1. The mixture was stirred at room temperature for 3 hours. The solvent under reduced pressure was evaporated to obtain the inclusion complex. (71% yield) with 90% purity.

[0154] The inclusion complex of chiral compounds of formula I with EDTA can enhance the bioavailability and stability of chiral sulfoxide compounds, making it more effective for use in pharmaceutical formulations or as a dietary supplement.

Claims

Claims:

1. A green enantioselective sulfoxide compound(s) of Formula I:Formula I wherein n is an integer ranging from 1 to 6.

2. A process for green enantioselective synthesis of sulfoxide compound(s) of Formula I, comprising: a) preparing isothiocyanates compound(s) of Formula II from primary amineFormula-II wherein n is integer ranging from 1 to 6; b) preparing optically active sulfoxide compound(s) of Formula I by chiral oxidation of the isothiocyanates compound(s) of Formula IIFormula-I wherein n is integer ranging from 1 to 6.

3. The process as claimed in claim 2, wherein the optically active isomer is R isomer.

4. The process as claimed in claim 2, wherein the primary amine compounds of Formula III are selected from the group consisting of 2-(methylsulfanyl) ethan-l-amine,3- (methylsulfanyl)propan- 1 -amine, 4-(m ethyl sulfanyl)butan- 1 -amine, 5 -(methyl sulfanyl) pentan- 1 -amine.

5. The process as claimed in claim 2, wherein the isothiocyanates compounds of Formula II are selected from the group consisting of l-isothiocyanato-2-(methylsulfanyl)ethane; 1- isothiocyanato-3-(methylsulfanyl)propane; l-isothiocyanato-4-(methylsulfanyl)butane; 1- isothiocyanato-5-(methylsulfanyl)pentane.

6. The process as claimed in claim 2, wherein the chiral sulfoxide compounds of Formula I is selected from the group consisting of l-isothiocyanato-2-[(R)-methanesulfmyl]ethane; 1- isothiocyanato-3-[(R)-methanesulfinyl]propane; l-isothiocyanato-4-[(R)-methanesulfmyl] butane; l-isothiocyanato-5-[(R)-methanesulfmyl]pentane.

7. The process as claimed in claim 2, wherein the formation of isothiocyanates compounds of Formula II comprising the in situ formation of dithiocarbamate, followed by oxidation and purification.

8. The process as claimed in claim 2, wherein the formation of dithiocarbamate is carried out in presence of carbon disulfide and base tri ethyl amine, oxidation is carried out in presence of 35% hydrogen peroxide and polar aprotic solvent tetrahydrofuran and subsequent purification is carried out in presence of sodium chloride.

9. The process as claimed in claim 2, wherein the chiral oxidation of isothiocyanates compounds of Formula II is carried out in presence of chiral sulfonic acid; wherein the chiral sulfonic acid is 10-Camphor sulfonic acid.

10. The process as claimed in claim 2, wherein the green solvents are selected from water, acetone, ethanol, 1 -propanol, isopropanol, toluene, ethyl acetate, methanol, t-butanol, 1- butanol or mixtures thereof.

11. The process as claimed in claim 2, wherein the specific optical rotation of chiral compound of Formula I is -76°C±3.

12. The process as claimed in claim 2, wherein the enantiomeric excess of R isomer is 90% to 99%.

13. The process as claimed in claim 2, wherein the compound of formula I is useful for treatment of structural, biochemical or electrical abnormalities in the brain, spinal cord, peripheral nerves, nerve roots, autism (ASD), autonomic nervous system, epilepsy, Alzheimer’s disease, dementia, cerebrovascular diseases stroke, migraine, cardiovascular disorder, diabetes, dyslipidemia, multiple sclerosis, Parkinson's disease, neuroinfectious, brain tumours, traumatic disorders.

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