A process for preparation of gabapentin

Abstract

The present disclosure relates to an industrially feasible and economically viable process for preparation of Gabapentin of formula (I) which is shown below: (I)

Description

Attorney Docket No.: 101504.00003 A PROCESS FOR PREPARATION OF GABAPENTIN CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The instant application claims the benefit of priority to U.S. ProvisionalApplication No.63 / 709,080, filed on October 18, 2024, and U.S. Provisional No.63 / 776,010, filed on March 21, 2025, the disclosures of which are incorporated herein by reference. FIELD OF THE PRESENT DISCLOSURE

[0002] The present disclosure relates to a process for preparation of Gabapentin (I).BACKGROUND OF THE PRESENT DISCLOSURE

[0003] Gabapentin is chemically, 1-(aminomethyl)-1-cyclohexane acetic acid, having the structure shown below:

[0004] Gabapentin is an anticonvulsant medication and is useful in treating epilepsy and various other cerebral disorders. It was first described by Warner-Lambert Co. in U.S. Pat. No.4,024,175.

[0005] A process for the preparation of gabapentin is described in U.S. Pat. No. 4,087,544. It involves converting 1,1-cyclohexanediacetic acid (II) to its anhydride (III) followed by treatment with ammonia to give 1, 1-cyclohexanediacetic acid monoamide (IV), which is subjected to Hofmann reaction to obtain Gabapentin (I).

[0006] Several methods for preparing Gabapentin by a multi-step synthesis based on cyclohexanone functionalization have also been described. These include the preparation of a nitrile, dicarboxylic acid and / or nitro carboxylic acid intermediates of Gabapentin, which are then subjected to catalytic hydrogenation to yield the free amino acid, often without the need to prepare the amine salt intermediate of Gabapentin. Such methods are described in U.S. Pat. No.5,068,413, U.S. Pat. No.5,091,567, U.S. Pat. No.5,095,148, U.S. Pat. No.5,132,451, EP0414275A2 and Helvetica Chimica Acta (1999), 73: 309-14.

[0007] While there are a variety of methods for preparing and purifying Gabapentin known in the art, these methods have many disadvantages. For example, the conversion of 1,1-cyclohexanediacetic (CDA) acid into Gabapentin via the Curtius or Lossen rearrangements are industrially impractical due to the inherent production of dangerous intermediates (explosive azides) or expensive, laborious work-up (Lossen).

[0008] Most of the industrial manufacturing processes existing today involve 1,1 cyclohexanediacetic acid (CDA) as the starting material. CDA by itself being an extremely hazardous environmental pollutant, the synthesis of the same uses a very highly carbon inefficient method.

[0009] The patents CN101475466B and GB898692A describe the synthesis of CDA involving condensing cyclohexanone (V) with 2.2 equivalents of ethylcyano acetate in the presence of ammonia in the large volume of methanol, at low temperature for over 48-92 hours. The resultant cyclic imide salt (VI) is treated with a large volume of conc. H2SO4at over 140 °C for a number of hours. The reaction emits a large amount of CO2 apart from the H2SO4, which needs to be diluted with a large amount of water for precipitating the CDA (II).

[0010] The above method generates a large volume of methanol and wastewater mixed with H2SO4, ammonium salts and organics apart from resulting in a very dark colour solution. A large amount of gas evolution is also observed during hydrolysis.

[0011] Around seven times of 70% H2SO4is used for an output of 1 part of CDA, which again is diluted with another 2 times of water for precipitation, leading to 21 volumes of dilute H2SO4which needs to be neutralized with caustic soda before treatment. Thus, thismanufacturing process of CDA is not only highly polluting, but also time and energy consuming.

[0012] The other intermediates involve use of toxic material such as sodium cyanide and nitromethane. Moreover, reduction of nitro methyl function to amino methyl in the last step of synthesis to gabapentin poses problems, related to aliphatic nitro reduction.

[0013] All processes based on 1,1-cyclohexanediacetic acid derivatives involve the preparation of the corresponding intermediates (amino acid salts and crude products) as aqueous solutions, requiring large volumes of liquid, which is impractical for an industrial synthesis. Moreover, the ion exchange step used in these processes requires large amounts of demineralized water, dedicated, large chromatographic columns filled with ion exchange resin, using specialized and costly equipment (i.e., pressure pumps and pipes, addition and receiving vessels, etc.), which is time-consuming and commercially impractical. The isolation of crude amino acids from aqueous solutions by evaporation at temperatures below 40-50 °C requires dedicated equipment, high energy, time consuming and generating large volume of effluent. Alternative methods that do not proceed via the amino acid salts (such as hydrochlorides or sulphates) include multistep laborious syntheses and catalytic hydrogenations that require special, dedicated equipment. Such methods usually involve the presence of the lactam intermediate, and its conversion to the desired, free amino acid is not immediate in neutral conditions and often remains as an undesired impurity in the final product.

[0014] Therefore, a need exists for an economical, facile, and greener industrial procedure to prepare highly pure, pharmaceutical grade Gabapentin. SUMMARY OF THE PRESENT DISCLOSURE

[0015] The problem addressed by the present disclosure is that of providing an improved, efficient, economic and an industrially viable process for preparation of Gabapentin (I). One example of the present disclosure is that the method for synthesizing Gabapentin (Formula I) includes the following steps: (i) Reacting 1-hydroxy-2-oxaspiro[4.5]decan-3-one (Formula VII) with a hydroxylamine, such as hydroxylamine hydrochloride, in a solvent and in the presence of a base to produce 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (Formula XV).(ii) Reducing compound (XV) in a solvent with alcoholic ammonia to yield Gabapentin(Formula I)

[0016] Another example of the present disclosure is a process for preparation of 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII), by (a) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(c) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1-hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII) (D represents delta, which represents heating);

[0017] Yet another example of the present disclosure is to synthesise of 1-hydroxy-2- oxaspiro [4.5]decan-3-one of formula (VII); a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);b) acetalizatilising Cyclohexanecarboxaldehyde (VIII) in presence of a catalyst and in an alkanol solvent to provide dialkyloxymethylcyclohexane of formula (XII) .c) heating dialkyloxymethylcyclohexane compound of formula (XII) in presence of a catalyst to provide (alkyloxymethylene)cyclohexane of formula (XIII)d) reacting the (alkyloxymethylene)cyclohexane of formula (XIII) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2 alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2 alkyloxyspiro[2.5]octane- 1-carboxylate (XIVB);e) treating the mixture of alkyl trans-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVB) with an acid to obtain 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);

[0018] Another example wherein the compounds (XA) and compound (XB) areutilized in the synthesis of gabapentin.

[0019] Yet another example of the present disclosure is a process for preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII); a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);(b) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(c) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(d) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII) (D represents delta, which represents heating);

[0020] Another example of the present disclosure involves the preparation of gabapentin using a flow chemistry method. This approach offers significant industrial advantages, including ease of reaction, cost-effectiveness, and suitability for large-scale production.

[0021] An alternative example describes a flow chemistry process for synthesizing gabapentin, comprising the following steps: i. Cyclohexane Carboxaldehyde (VIII): Cyclohexene-3-carboxyaldehyde (XI) ishydrogenated using a palladium on carbon catalyst at 90°C and 15 bar, forming Cyclohexane Carboxaldehyde (VIII).ii. Cyclohexylidenemethylacetate (IX): Cyclohexane Carboxaldehyde (VIII) reacts with acetic anhydride and potassium carbonate, processed at 135°C in a dynamic reactor to produce Cyclohexylidenemethylacetate (IX). iii. (Acetyloxy)spiro[2.5]octane-1-carboxylate (XA & XB): Cyclohexylidenemethylacetate (IX) undergoes reaction with ethyldiazoacetate in a copper-catalysed reactor at 100°C, followed by fractional distillation for purification. iv. 1-Hydroxy-2-oxaspiro[4.5]decan-3-one (VII): (Acetyloxy)spiro[2.5]octane-1- carboxylate is hydrolyzed in a flow reactor at 120°C with hydrochloric acid, yielding 1-Hydroxy-2-oxaspiro[4.5]decan-3-one (VII). v. 1-[(Hydroxyimino)methyl]cyclohexaneacetic Acid (XV): 1-Hydroxy-2- oxaspiro[4.5]decan-3-one is reacted with hydroxylamine hydrochloride and sodium carbonate in methanol at 45°C, followed by acidification to isolate the product. vi. Gabapentin (I): 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV) is hydrogenated over Raney nickel at 100°C and 20 bar in a methanol solution, yielding Gabapentin (I) after final purification; Herein the reaction mixture is repeatedly circulated through the reactor to achieve full conversion into the target compound. Unreacted starting materials are separated using fractional distillation, ensuring a higher purity of the final product. The flow chemistry approach facilitates efficient reactions, reduces costs, and enhances scalability for industrial production DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

[0022] It is to be understood that the present disclosure is not limited to methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for describing the particular examples only and is not intended to limit the scope of the present disclosure.

[0023] It is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this present disclosure belongs. Further, it is to be understood that the present disclosure is not limited to the methodologies and materials similar, equivalent to those described herein can be used in the practice, or testing of the present disclosure, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as “including,” “containing,” “comprising,” “having” and the like, means “including without limitation” andshall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Examples of the disclosure are not mutually exclusive but may be implemented in various combinations. The described examples of the disclosure and the disclosed examples are given for the purpose of illustration rather than limitation of the disclosure as set forth in the appended claims. Further, the terms disclosed examples are merely exemplary methods of the disclosure, which may be embodied in various forms.

[0024] 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 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.

[0025] The term “heating”, as used herein, is heating the solution gradually to a temperature in the range of 60-90°C.

[0026] Ranges of values are disclosed herein. The ranges set out a lower limit value and an upper limit value. Unless otherwise stated, the ranges include the lower limit value, the upper limit value, and all values between the lower limit value and the upper limit value, including, but not limited to, all values to the magnitude of the smallest value (either the lower limit value or the upper limit value) of a range. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “0.1% to 5%” should be interpreted to include not only the explicitly recited values of 0.1% to 5%, but also, unless otherwise stated, include individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5% to 1.1%; 0.5% to 2.4%; 0.5% to 3.2%, and 0.5% to 4.4%, and other possible sub-ranges) within the indicated range. It is also understood (as presented above) that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about, it will be understood that the particular value forms a further disclosure. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0027] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0028] As used herein, unless otherwise stated or indicated, “s” refers to second(s), “min” refers to minute(s), and “h” refers to hour(s).

[0029] The phrase “therapeutically effective amount” is used herein to mean an amount sufficient to reduce by at least about 15 percent, preferably by at least 50 percent, more preferably by at least 90 percent, and most preferably prevents oxidative stress in the individual. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in the individual.

[0030] As used herein, unless otherwise stated, the term “group” refers to a chemical entity that is monovalent (i.e., has one terminus that can be covalently bonded to other chemical species), divalent, or polyvalent (i.e., has two or more termini that can be covalently bonded to other chemical species). The term “group” also includes radicals (e.g., monovalent and multivalent, such as, for example, divalent radicals, trivalent radicals, and the like). Illustrative examples of groups include:

[0031] As used herein, unless otherwise indicated, the term “alkyl” or “alkyl group” refers to branched or unbranched, linear saturated hydrocarbon groups and / or cyclic hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, propyl groups, butyl groups, isopropyl groups, tert-butyl groups, cyclopropyl groups, cyclopentyl groups, cyclohexyl groups, and the like. Alkyl groups are saturated groups, unless it is a cyclic group. For example, an alkyl group is a C1to C40alkyl group, including all integer numbers of carbons and ranges of numbers of carbons therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21,C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, and C40). The alkyl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated aryl groups, alkoxide groups,amine groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alcohol groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof.

[0032] As used herein, the term “cycloalkyl” or “cycloalkyl group” refers to a cyclic hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl groups. Cycloalkyl groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three substituents. Each substituent is independently chosen from alkyl, -NH2, oxo (=O), phenyl, haloalkyl (e.g., -CF3), halo (e.g., -F, -Cl, -Br, -I), alkoxy, and –OH groups. Additionally, alkyl substituents may be substituted with various other functional groups. Additional non-limiting examples include aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated aryl groups, alkoxide groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof.

[0033] As used herein, unless otherwise indicated, the term “aryl” or “aryl group”refers to C5 to C30 aromatic or partially aromatic carbocyclic groups, including all integer numbers of carbons and ranges of numbers of carbons therebetween (e.g., C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29,and C30). An aryl group may also be referred to as an aromatic group. The aryl groups may comprise polyaryl groups such as, for example, fused rings, biaryl groups, or a combination thereof. The aryl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), aryl groups, alkoxides, carboxylates, carboxylic acids, ether groups, and the like, and combinations thereof. Examples of aryl groups include, but are not limited to, phenyl groups, biaryl groups (e.g., biphenyl groups and the like), fused ring groups (e.g., naphthyl groups and the like), hydroxybenzyl groups, tolyl groups, xylyl groups, and the like.

[0034] As used herein, the term “heteroaryl” or “hereteroaryl” refers to a monocyclic or bicyclic ring system comprising one or two aromatic rings and containing at least one nitrogen or oxygen atom in an aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one or two, substituents. Non-limiting examples of substituents include halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated arylgroups, alkoxide groups, amine groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alcohol groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof. Examples of heteroaryl groups include, benzofuranyl, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl groups, and substituents analogs of any of the foregoing heteroaryl groups.

[0035] The term ‘flow chemistry method’ as used herein, is a chemical reaction run in a continuously flowing stream rather than in batch production; i.e., a chemical process that involves pumping reactants through a system of tubes and reactors to perform a reaction.

[0036] Accordingly, the present disclosure relates to a process for the preparation of 1-hydroxy-2-oxaspiro [4.5] decan-3-one of formula (VII),comprising: a) treating a Cyclohexanecarboxaldehyde (VIII) with acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1 carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);c) treating the mixture of alkyl trans-2-acetoyloxyspiro[2.5]octane-1-carboxylate (XA) 5 and alkyl cis-2-acetoyloxyspiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1-hydroxy- 2-oxaspiro[4.5]decan-3-one of formula (VII);

[0037] The acid anhydride used in step (b) is selected from acetic anhydride, propionic anhydride, and butanoic anhydride. In various examples, the acid anhydride is acetic anhydride.

[0038] The base used in step (a) is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 151,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0039] The alkyl diazoacetate used in step (b) is selected from methyl diazoacetate, ethyl diazoacetate, n-propyl diazoacetate, isopropyl diazoacetate, n butyl diazoacetate, isobutyl diazoacetate, sec-butyl diazoacetate, tert-butyl diazoacetate, n pentyl diazoacetate, n- hexyl diazoacetate, and cyclohexyl diazoacetate.

[0040] The catalyst used in step (b) for cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate, and organometallic complexes of copper, rhodium.

[0041] The acid used in step (c) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluoride in ether.

[0042] The whole synthetic scheme of preparation of compound of formula (VII) according to the present disclosure can be represented as below:

[0043] In another aspect, the present disclosure relates to a process for the 1-hydroxy- 2-oxaspiro [4.5]decan-3-one of formula (VII),comprising: a) reducing the Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);b) acetalizatilising Cyclohexanecarboxaldehyde (VIII) in presence of a catalyst and in an alkanol solvent to provide dialkyloxymethylcyclohexane of formula (XII)c) heating dialkyloxymethylcyclohexane compound of formula (XII) in presence of a catalyst to provide (alkyloxymethylene)cyclohexane of formula (XIII).d) reacting the (alkyloxymethylene)cyclohexane of formula (XIII) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2 alkyloxyspiro[2.5]octane-1- carboxylate (XIVA) and alkyl cis-2 alkyloxyspiro[2.5]octane-1-carboxylate (XIVB);e) treating the mixture of compound trans- and cis alkyl 2-alkyloxyspiro[2.5]octane carboxylates (XIVA) and compound (XIBB) with an acid to obtain 1-hydroxy-2 oxaspiro[4.5]decan-3-one of formula (VII);

[0044] The reduction of compound of formula (XI) in step (a) is carried out using catalytic hydrogenation via hydrogen gas in the presence of Raney Nickel, Pd / C, Rh / C, or Ru / C. In various methods, catalytic hydrogenation is performed via utilizing Raney Nickel, Pd / C, Rh / C, and Ru / C, and a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid, or hydrazinium monoformate. Preferably, the reducing agent is Pd / C and hydrogen gas.

[0045] The acetalization catalysts used in step (b) may be a mixture of N Chlorosuccinimide (NCS) and Thiourea, inorganic acids selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methane sulfonic acid and acidic resins respectively.

[0046] The alkanol solvent used in step (b) is selected from methanol, ethanol, n propanol, n-butanol, and n-hexanol.

[0047] The acetal compound XII conversion to vinyl ether XIII in step (c) may be catalysed by acids, bases, or neutral alumina.

[0048] The alkyl diazoacetate used in step (d) is selected from methyl diazoacetate, ethyl diazoacetate, n-propyl diazoacetate, isopropyl diazoacetate, n butyl diazoacetate, isobutyl diazoacetate, sec-butyl diazoacetate, tert-butyl diazoacetate, n pentyl diazoacetate, n- hexyl diazoacetate, and cyclohexyl diazoacetate.

[0049] The catalyst used in step (d) for cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate, and organometallic complexes of copper, rhodium.

[0050] The acid used in step (e) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, and boron trifluoride in ether.

[0051] The whole synthetic scheme of preparation of compound of formula (VII) according to the present disclosure can be represented as below:

[0052] In various examples, R and R1 is an alkyl group. Examples of group include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, and n-hexyl.

[0053] In another aspect, the present disclosure provides a process for the preparation of Gabapentin (I):comprising: a) reacting the 1-hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII) with a hydroxylamine, preferably hydroxylamine HCl in a solvent and in presence of a base to obtain 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);b) reducing the compound (XV) in a solvent and in a presence of alcoholic ammonia to provide Gabapentin (I).

[0054] The base used in step (a) is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; and alkali metal salts of lower aliphatic acids like formate, acetate, and propionate.

[0055] The solvent used in step (a) and step (b) may be an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4 dioxane, 1,2-dioxane, an 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol; water; or any mixture thereof.

[0056] The reduction of the compound of formula (XV) in step (b) is carried out in a solvent, in the presence of alcoholic ammonia and using a reducing agent to obtain Gabapentin (I).

[0057] The solvent used for reducing compound of formula (XV) in step (b) may be an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2 methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; water; or a mixture thereof.

[0058] In various examples, the solvent used for reducing compound of formula (XV) is an alcoholic solvent, such as, for example, methanol.

[0059] The solvent used for the preparation of alcoholic ammonia solution in step (b) may be selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol. In various examples, the solvent used is methanol.

[0060] The reduction of compound of formula (XV) in step (b) is carried out using reducing agent selected from Raney Nickel, Pd / C, Pt / C, Rh / C in presence of H2, zinc dust in presence of acid and sodium borohydride. The reduction of the compound can be carried out using reducing agent and suitably, in the presence of Lewis acid selected from AlCl3, LiCl, and BF3 etherate. The reduction may occur in the presence and of hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate. Preferably, the reducing agent is Pd / C and hydrogen gas or Raney nickel and hydrogen gas.

[0061] The whole synthetic scheme of preparation of compound of formula (I) according to the present disclosure may be represented as below:

[0062] According to the present disclosure, purification of Gabapentin (I), comprises: (i) treating Gabapentin in a mixture of water and an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA);(ii) optionally heating the mixture of step (a); (iii) adding isopropanol (IPA) to the solution; (iv) cooling and filtering the obtained precipitate; (v) washing the precipitate with alcoholic solvent selected from methanol, ethanol, isopropanol (IPA); and (vi) drying the obtained solid of step (v) to get pure solid as Gabapentin (I).

[0063] Another alternate example of the present disclosure involves, a method for synthesizing gabapentin using a flow chemistry approach, emphasizing the process’s advantages for industrial applications. Flow chemistry involves continuous processing, where chemical reactions occur as the reactants flow through a reactor, rather than in traditional batch processing. This method is highlighted for its efficiency, cost-effectiveness, and scalability, making it particularly suitable for large-scale production of gabapentin.

[0064] An alternative example describes a flow chemistry process for synthesizing gabapentin, comprising the following steps: vii. Cyclohexane Carboxaldehyde (VIII): Cyclohexene-3-carboxyaldehyde (XI) is hydrogenated using a palladium on carbon catalyst at 90°C and 15 bar, forming Cyclohexane Carboxaldehyde (VIII). viii. Cyclohexylidenemethylacetate (IX): Cyclohexane Carboxaldehyde (VIII) reacts with acetic anhydride and potassium carbonate, processed at 135°C in a dynamic reactor to produce Cyclohexylidenemethylacetate (IX). ix. (Acetyloxy)spiro[2.5]octane-1-carboxylate (XA & XB): Cyclohexylidenemethylacetate (IX) undergoes reaction with ethyldiazoacetate in a copper-catalysed reactor at 100°C, followed by fractional distillation for purification. x. 1-Hydroxy-2-oxaspiro[4.5]decan-3-one (VII): (Acetyloxy)spiro[2.5]octane-1- carboxylate is hydrolyzed in a flow reactor at 120°C with hydrochloric acid, yielding 1-Hydroxy-2-oxaspiro[4.5]decan-3-one (VII). xi. 1-[(Hydroxyimino)methyl]cyclohexaneacetic Acid (XV): 1-Hydroxy-2- oxaspiro[4.5]decan-3-one is reacted with hydroxylamine hydrochloride and sodium carbonate in methanol at 45°C, followed by acidification to isolate the product. xii. Gabapentin (I): 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV) is hydrogenated over Raney nickel at 100°C and 20 bar in a methanol solution, yielding Gabapentin (I) after final purification.

[0065] In this method, the reaction mixture is cycled multiple times through the reactor to ensure complete conversion to the desired compound. Fractional distillation isemployed to separate any unreacted starting materials, thus enhancing the purity of the final product.

[0066] This continuous-flow methodology offers high efficiency, minimizes waste, eliminates the need for solvents, and ensures consistent, reproducible results. It is a highly effective strategy for large-scale production of gabapentin and related compounds.

[0067] The process of the instant disclosure provides all liquid-liquid reactions, with very low waste generation, both solid and gaseous. Thus, this process brings in an environmentally friendly green process for the manufacture of an important large volume of drug such as gabapentin with highly effective carbon utility.

[0068] According to the present disclosure, the overall yield of compound of formula (I) as obtained by using the process of the present disclosure is at least about 80% yield with purity of at least about 99.6% by HPLC. Thereby, the practicability of the reaction is greatly enhanced at both the laboratory scale and the industrial scale.

[0069] The following Statements are intended to provide examples of the present disclosure. They are not intended to be limiting in any way. Statement 1. A process for preparation of Gabapentin of formula (I),comprising: (a) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., hydroxylamine HCl) in a solvent and in presence of a base to obtain 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);(b) reducing the compound (XV) in a solvent and in a presence of alcoholic ammonia to provide Gabapentin (I). Statement 2. A process according to Statement 1, wherein the preparation of 1-hydroxy-2- oxaspiro [4.5]decan-3-one of formula (VII);comprises: (a) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(c) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);Statement 3. A process according to Statement 1, wherein the preparation of 1-hydroxy-2- oxaspiro [4.5]decan-3-one of formula (VII);comprises: a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);(b) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(c) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(d) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);Statement 4. A process according to Statement 1, wherein the preparation of 1-hydroxy-2- oxaspiro [4.5]decan-3-one of formula (VII);comprises: a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);b) acetalizatilising Cyclohexanecarboxaldehyde (VIII) in presence of a catalyst and in an alkanol solvent to provide dialkyloxymethylcyclohexane of formula (XII) .c) heating dialkyloxymethylcyclohexane compound of formula (XII) in presence of a catalyst to provide (alkyloxymethylene)cyclohexane of formula (XIII)d) reacting the (alkyloxymethylene)cyclohexane of formula (XIII) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2 alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2 alkyloxyspiro[2.5]octane- 1-carboxylate (XIVB);e) treating the mixture of alkyl trans-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVB) with an acid to obtain 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);. Statement 5. A process according to Statement 1, wherein, in (a) and (b), the solvent used is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, and 1,4 dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol; an aprotic solvent (e.g., esters) selected from ethyl acetate, acetonitrile, N,N- dimethyl formamide (DMF), N,N-dimethyl acetamide, and N-methylpyrrolidone (NMP); or an aromatic solvent selected from toluene and xylene; water; or a mixture thereof; in (a), the base is an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate, and caesium carbonate; alkali metal bicarbonate selectedfrom sodium bicarbonate and potassium bicarbonate; or organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and in (b), the alcoholic solvent used in the preparation of alcoholic ammonia solution is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol. Statement 6. A process according to Statement 2, wherein, in (a), the base is an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate, and caesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate and potassium bicarbonate; and an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); in (b), the alkyl diazoacetate is selected from methyl diazoacetate, ethyl diazoacetate, n- propyl diazoacetate, isopropyl diazoacetate, n-butyl diazoacetate, isobutyl diazoacetate, sec butyl diazoacetate, tert-butyl diazoacetate, n-pentyl diazoacetate, n hexyl diazoacetate, and cyclohexyl diazoacetate; in step (b) the catalyst used for cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate and organometallic complexes of copper, rhodium; (e.g., Cuprous salts, rhodium (II) acetate and organometallic complexes of copper (I) and(II) and rhodium (II)) and in (c), the acid used is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, and boron trifluoride in ether. Statement 7. A process according to Statement 4, wherein, in (a) the reducing agent used is selected from Raney Nickel, Pd / C, zinc dust in presence of acid and sodium borohydride, hydrogen gas, and a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate; in (b) the alkanol solvent is selected from methanol, ethanol, n-propanol, n butanol, and n- hexanol; in (c) the acetal compound XII conversion to vinyl ether XIII is catalysed by an acid catalyst, a base catalyst, or neutral alumina; in (d) the alkyl diazoacetate is selected from methyl diazoacetate, ethyl diazoacetate, n- propyl diazoacetate, isopropyl diazoacetate, n-butyl diazoacetate, isobutyl diazoacetate,sec butyl diazoacetate, tert-butyl diazoacetate, n-pentyl diazoacetate, n hexyl diazoacetate, and cyclohexyl diazoacetate; in (d) the catalyst used for the cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate, organometallic complexes of copper, and rhodium; in (b), the catalyst used is a mixture of N-Chlorosuccinimide (NCS) and Thiourea; and in (e), the acid used is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluoride in ether. Statement 8. A process as claimed in Statement 1, wherein, the preparation of Gabapentin (I),comprises the steps of: a) treating Cyclohexanecarboxaldehyde (VIII) with acetic anhydride in presence of potassium carbonate to obtain Cyclohexylidenemethyl acetate (IX);b) reacting Cyclohexylidenemethyl acetate (IX) with Ethyl diazoacetate in presence of copper-bronze to obtain a mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1- carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1 carboxylate (XB);c) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with hydrochloric acid to obtain 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);d) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., preferably hydroxylamine HCl) in a solvent and in methanol and in presence of sodium carbonate to obtain 1 [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);e) reducing compound (XV) in methanol with methanolic ammonia to provide Gabapentin (I).Statement 9. A process according to Statement 1 or Statement 8, wherein the purification of Gabapentin (I) which is obtained from step (b) of claim 1 and step (e) of claim 8, comprises the steps of: (i) contacting Gabapentin in a mixture of water and an alcoholic solvent to form a mixture; (ii) optionally heating the mixture of step (a); (iii) adding isopropanol (IPA) to the mixture; (iv) cooling and filtering the obtained precipitate; (v) washing the precipitate with an alcoholic solvent; and (vi) drying the obtained solid of step (v) to obtain pure solid as Gabapentin (I).Statement 10. A process according to Statement 9, wherein the alcoholic solvent used in (i)and (v) is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol.Statement 11. A process according to Statement 1 or Statement 8, wherein the compound of formula (I) obtained has a purity of at least 99% (e.g., 99.6) by HPLC.Statement 12. A process for preparing Gabapentin (formula (I))comprising: formation ofprior to the formation of gabapentin, wherein R is an alkyl group.Statement 13. A compound having the following structure:wherein R is an alkyl group selected from: methyl, ethyl, n-propyl, n-butyl, and n-hexyl.Statement 14. A process for preparation of Gabapentin of formula (I) utilizing a flowchemistry process,comprising: (a) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine in a solvent and in presence of a base to obtain 1- [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);(b) reducing the compound (XV) in a solvent and in a presence of alcoholic ammonia to provide Gabapentin (I).Statement 15. A process according to Statement 14, wherein the preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);comprises: (a) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(c) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);Statement 16. A process for the preparation of gabapentin (I) utilizing a flow chemistryprocesscomprises the steps of: a) treating Cyclohexanecarboxaldehyde (VIII) with acetic anhydride in presence of potassium carbonate to obtain Cyclohexylidenemethyl acetate (IX);b) reacting Cyclohexylidenemethyl acetate (IX) with Ethyl diazoacetate in presence of catalyst to obtain a mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1 carboxylate (XB);c) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with hydrochloric acid to obtain 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);d) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., preferably hydroxylamine HCl) in a solvent and in methanol and in presence of sodium carbonate to obtain 1 [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);e) reducing compound (XV) in methanol with methanolic ammonia to provide Gabapentin (I);.Statement 17. A process according to Statement 16, wherein the preparation of Cyclohexanecarboxaldehyde (VIII) compressing, reducing Cyclohex-3-enecarbaldehyde (XI);.Statement 18. A process for preparing gabapentin (I) using a flow chemistry process havingindustrial advantages, including ease of reaction, cost-effectiveness, and scalability for large-scale production, the method comprising: (a) cycling a reaction mass through a reactor multiple times under consistent conditions to achieve complete conversion of Cyclohex-3-enecarbaldehyde (XI) to cyclohexane-3- carboxaldehyde (VIII);(b)acetylating and isolating cyclohexane-3-carboxaldehyde (VIII) to produce cyclohexylidenemethylacetate (IX) as a colorless liquid with high purity through fractional distillation under reduced pressure; (c) reacting cyclohexylidenemethylacetate (IX) with alkyl diazoacetate in the presence of a catalyst under flow mode to synthesize (acetyloxy)spiro[2.5]octane-1-carboxylate (XA, XB), followed by purification via fractional distillation to separate starting materials; (d) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid by pumping the mixture with an acid at flow rate of 1ml / min into a reactor to obtain 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII); (e) converting 1-hydroxy-2-oxaspiro[4.5]decan-3-one (VII) to gabapentin (I) through an intermediate, 1-[(hydroxyimino)methyl]cyclohexaneacetic acid (XV); wherein each reaction stage is optimized to ensure high efficiency, consistent yields, and suitability for industrial-scale production.

[0070] The present disclosure is further illustrated by the following examples which are provided to be exemplary of the present disclosure, and are not intended to limit its scope. While the present disclosure has been described in terms of its specific examples, certain modifications, and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure. EXAMPLES Example 1 Preparation of Cyclohexane carboxaldehyde (VIII).

[0071] Cyclohex-3-enecarbaldehyde (XI) 100 g (100 g, 0.90 moles) was reduced with 5 % Palladium on carbon RD-454(1.5 g) at 75-80 °C under 15-20 kg / cm2 hydrogen pressure. The neat reaction progress was monitored by GC (gas chromatography) and after 2.0 hours 98.08 % product was obtained. The reaction mass was unloaded from the autoclave, the catalyst was filtered, and washed with methanol (20 ml). The filtrate was evaporated under reduced pressure to give a pale green liquid of Cyclohexane carboxaldehyde (VIII) (100.50 g, 98.03 %); Purity 98.08 % by GC; Boiling Point: 161-163 °C.Example 2 Preparation of Cyclohexane carboxaldehyde (VIII).

[0072] A neat solution of Cyclohexene-3-carboxyaldehyde (XI) (150 gm, 1.36 moles) was passed through the prepacked 10 % palladium on carbon (50%wet, 150 gm) in catalytic reactor at liquid flow rate 5.2 ml / min with 400 SCCM / min of hydrogen gas flow at pressure 15 bar and temperature 90°C±2°C. Collected reaction mass was recycled from same reactor with same conditions for 5 more time to convert complete starting material to 3-cyclohexane carboxyaldehyde. After six cycles, reaction mass was collected and cooled to room temperature to give a pale green liquid of Cyclohexane carboxaldehyde (VIII) (141 g, 95 %); Purity > 92 pa % by GC; Boiling Point: 161-163°C. Example 3 Preparation of Cyclohexylidenemethylacetate (IX)

[0073] Potassium carbonate (307.74 g, 2.23 mol) was added to a mixture of cyclohexane carboxaldehyde (VIII) 500.00 g (4.46 mol), and Acetic anhydride (910.64 g, 8.92 mol, freshly distilled) and maintained at 135-140 °C for 2 hours. The reaction mass was cooled to room temperature and gradually added to 800.00 ml of chilled water to the mass was allowed to attain room temperature and the product was extracted using dichloromethane (1600.00 ml, 3.2 vol). The dichloromethane layer was washed using demineralized (DM) water (800.00 ml, 1.6 vol). The dichloromethane layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a pale-yellow liquid of crude Cyclohexylidenemethylacetate (IX) (750.00 g, Purity-89.57%). The crude product was distilled under reduced pressure to obtain pure Cyclohexylidenemethylacetate (IX) (556.87 g, 81.00 %); Purity 99.20 % by GC; Boiling point 85° C (13 mm Hg). Example 4 Preparation of Cyclohexylidenemethylacetate (IX).

[0074] To a solution of cyclohexane carboxyladheyde (VIII) (200g, 1eq, 1.78 moles) in acetic anhydride (272.9 g, 1.5 eq, 2.67 moles), dried potassium carbonate (61.5 g, 0.25 eq,0.445 moles) was added. The suspension was stirred for 30 min at 25±5°C. A thick homogeneous suspension was passed through 40 mL dynamic reactor with flow rate 6.66 mL / min at temperature 135±3°C. Reaction mass was collected and cooled to 25±5°C. To the above reaction mass Dichloromethane (DCM, 600 mL, 3V) was added and stirred for 1h at 0±5°C. Precipitated solid was collected by filtration, washed with Dichloromethane (DCM, 400 mL, 2V) and dried to yield 86.3 g (99 %) of Potassium acetate. The Filtrate DCM layer were combined and subjected for fractional distillation. The first fraction was obtained as DCM (328 g, 73%) at 30°C with reduced pressure 100 mmHg. The second fraction was obtained as Acetic acid (98 g, 92%) at 70°C with reduced pressure 100 mmHg. The third fraction was obtained as acetic anhydride (33g, 73%) at 85°C with reduced pressure 100 mmHg. The fourth fraction was obtained as product (Cyclohexylidenemethylacetate, colourless liquid, 241.1 g, 88%, 98 pa % purity by GC) at 140°C with reduced pressure 100 mmHg. The reaction mass was cooled to obtained residue of impurities (59g). Above isolated fourth fraction was used as such for next stages without any purification. Example 5 Preparation of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA), Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB).

[0075] Ethyldiazoacetate (167.0 g, 1.46 mol) in Toluene (20 %) was added drop wise to the slurry of Cyclohexylidenemethylacetate (451.40 g, 2.92 mol), freshly prepared Cu- bronze (23.80 g) at 100-105 °C over nine hours and stirred for another one hour at the same temperature. It was then cooled to room temperature and filtered. The filtrate comprised Toluene, unreacted vinyl acetate, and a cyclo propyl compound. The filtrate was distilled atmospherically to remove Toluene under vacuum (50.00 millibar) at 40-45 °C. Then the temperature was increased to 145-150 °C to recover unreacted Vinyl acetate (258.00 g). A brown color liquid mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate(XA), Ethyl cis-2 (acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) (295.00 g, 84.04 %) resulted; Boiling point 295-305°C (760 mm Hg). Example 6 Preparation of (acetyloxy)spiro[2.5]octane-1-carboxylate) (XA & XB).

[0076] Preparation of (acetyloxy)spiro[2.5]octane-1-carboxylate) (XA & XB), (Flow Mode) using premixed solution of vinyl acetate and EDA solution in toluene in CSTR.

[0077] The premixed solution of Cyclohexylidenemethylacetate (50 g, 1 eq, 0.0648 moles) with ethyl diazoacetate solution in toluene (0.5 eq, 24 % w / w assay by HPLC) was pumped through pump-A to the CSTR containing copper bronze catalyst (freshly prepared 2.5g,) and 2 ml of cyclohexylidenemethylacetate (CSTR equipped with heating coil) from the bottom inlet with pump flow rate 5 mL / min at temperature 100°C. The calculated retention time were about 10 min and with maintaining temperature, stirring and pump flow, experiment was run ~25 min. During the run, samples were collected at different time interval (10 min, 20 min and 25 min). Collected samples and CSTR containing reaction mass were submitted for GC analysis to confirm the reaction of starting material and product formation. Based on all sample results (shows about ~34 pa % of starting material and ~58 pa% of product), all fractions were mixed (total about 123 mL), filtered to remove catalyst, bed washed with 20 ml toluene and collected filtrate were subjected for fractional distillation.

[0078] The first fraction was collected as toluene (63 g, 95% recovery) at temperature 45°C with reduced pressure at 100 mmHg. The second fraction collected as recovered starting material (12 g, 66 % recovery, 91.80 pa % purity by GC) at temperature 145°C with reduced pressure 100 mmHg. The third fraction collected as again recovered starting material (4.4 g, 24 % recovery, 88.46 pa % purity by GC) at temperature 155°C with reduced pressure 100 mmHg, the reaction mass was cooled to room temperature to yield residue of acetyloxy spiro[2.5]octane-1-carboxylate (Compounds XA & XB) as a brown colour liquid (40 g, >100 %, 85.95 pa % purity by GC). Example 7 Preparation of Copper-Bronze.

[0079] Zinc dust (16.00 g, 0.24 mol) and copper sulfate pentahydrate (80.00 g, 1.30 mol) were added to water (300.00 ml) and a brown color slurry mass obtained was maintained for 30 minutes at room temperature. The solid was filtered, washed using water (2x 100.00 ml), acetone (3 x 20.00 ml), and ethanol (3 x 20.00 ml). The material was removed and dried under vacuum to get copper bronze (16.00 g). Example 8 Preparation of Ethyldiazoacetate (EDA).

[0080] Water (600 ml) and sodium tetraborate (30.90 g, 0.08 mol) was stirred at room temperature, to which was added sodium nitrite (156.19 g, 2.26 mol) and Ethyl glycinate hydrochloride (300.00 g, 2.15 mol) the mass was stirred at room temperature to get a clear solution.600.00 ml of toluene was added to the reaction mass and cooled to 0-5 °C.2 % phosphoric acid (1500.00 ml) was added drop wise to the reaction mass and the temperature was maintained below 20 °C. After complete addition, the pH of the aqueous layer was checked, and it was about 3.60. The mass was allowed to settle, and the aqueous and Toluene layers were separated. The toluene layer was washed using water (300.00 ml) and was then washed with sodium bicarbonate solution (2 x 600 ml). The concentration of EDA Solution in toluene was determined by HPLC and it was 20 % (w / w). Example 9 Preparation of Ethyl diazoacetate (EDA) solution in toluene.

[0081] To the clear solution of sodium tetraborate (20.60 g, 0.037 eq, 0.05 moles) and sodium nitrite (104.12g, 1.05 eq, 1.50 moles) in water (400 mL, 2V), Glycine ethyl ester HCl salt (200 g, 1 eq, 1.44 moles) was added and stirred for 60 min at 25-30°C. The obtained clear solution was pumped through pump-A at flow rate 5.6 ml / min and the 2% phosphoric acid aqueous solution pumped through pump-B at flow rate 4.4mL / min to the 10 mL liquid- liquid reactor at temperature 0±5°C. The reaction mass was quenched at outlet of the reactor with toluene (pumped through pump-C) at flow rate 2.2 mL / min. The reaction mass was collected, and pH of the aqueous layer was found about 3.6. layers were separated and to the toluene layer was washed with water (200 mL, 1V) followed by 10% aqueous sodium bicarbonate (400 mL x2 times, 4V). Separated organic layer (toluene layer) was dried over anhydrous sodium sulphate to yield ethyl diazo acetate solution in toluene. The obtained solution was analysed for assay by HPLC and found about 20 %w / w assay. The prepared solution (210 mL, 20 %w / w assay by HPLC) was used for next stage without any further purification. Example 10Preparation of 1-Hydroxy-2-oxaspiro[4.5] decan-3-one (VII).

[0082] Hydrochloric acid (6 N, 1180 ml, 4 vol) was added to (XA) and (XB) (295.00 g, 1.22 mol). The reaction mass was stirred at reflux temperature (100-105 °C) for 3 hours. After 3 hours, the reaction mass was cooled to room temperature, DM water was added (2950.00 ml, 10 vol) and the reaction mass was heated to reflux temperature (100-105 °C) for 5 hours. After 5 hours, the reaction mass was allowed to cool to room temperature. DCM (885.00 ml, 3 vol) was charged, and reaction mixture was stirred for 15 minutes after which the layers were separated. The aqueous layer was again extracted using dichloromethane (700.00 ml, 2.37 vol). The dichloromethane layers were combined, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to get crude 1-Hydroxy-2- oxaspiro [4.5] decan-3-one. Hexanes (530.00 ml, 1.80 vol) were added to the crude stirred at room temperature for 30 minutes, the solid was filtered (yield of 157.00 g), purity: 90.79 % by HPLC. Cyclohexane (1413.00 ml, 4.79 vol) and the crude solid (157.00 g) were stirred at reflux temperature to get a clear solution. Charcoalization was done at the same temperature, filtered and the filtrate was cooled to 0-5 °C and maintained at the same temperature for one hour. The solid was filtered and washed using pre-chilled cyclohexane (150.00 ml). The solid was unloaded and dried under vacuum at 50-55 °C to get pure 1-Hydroxy-2-oxaspiro [4.5] decan-3-one (VII) (145.00 g, 69.00 %), purity 98.27 % by HPLC, Melting point: 95-100 °C. D in the scheme represents delta, which represents heating. Example 11 Preparation of 1-Hydroxy-2-oxaspiro[4.5] decan-3-one (VII).

[0083] The clear 50% solution of acetyloxy spiro[2.5]octane-1-carboxylate (Compounds XA & XB) (40g, 1eq, 0.17 moles) in Isopropyl alcohol (40 mL, 1V) was pumped through pump-A at flow rate 1 mL / min and the 6N aqueous solution of Hydrochloric acid (80 mL) was pumped through pump-B at flow rate 1 mL / min. Both the pump flow was connected to 10 mL reactor and the reaction was performed at 120°C with retention time 5min. The collected reaction mass was cooled to 25-30°C. The IPA was removed by concertation under reduced pressure at 45-50°C. To the obtained residue, DCM (120 ml, 3 vol) was added, and reaction mixture was stirred for 15 minutes after which the layers were separated. The aqueous layer was again extracted using dichloromethane (95 ml, 2.37 vol). The dichloromethane layers were combined, dried over sodium sulphate, filtered, and filtrate was evaporated under reduced pressure to get crude 1-Hydroxy-2-oxaspiro [4.5] decan-3-one. Hexanes (72 ml, 1.80 vol) were added to the crude and stirred at room temperature for 30 minutes, the solid was filtered to yield crude product as off white solid. Cyclohexane (192 ml, 4.79 vol) and Crude solid were stirred at reflux temperature to get clear solution. Charcoalization was done at the same temperature, filtered and the filtrate was cooled to 0-5° C and maintained at the same temperature for one hour. Precipitated solid were collected by filtration and washed with pre chilled cyclohexane (25 ml). The solid was unloaded and dried under vacuum at 50-55° C to get pure 1-Hydroxy-2-oxaspiro [4.5] decan-3-one (VII) (24.1 g, 82 %), purity 99.8 pa % by HPLC, Melting point: 95-100°C. Example 12 Preparation of dimethoxymethylcyclohexane (XII).

[0084] Cyclohexane carboxaldehyde (VIII) 405 g (3.61 moles) was treated with 33.74 g of N-Chloro Succinimide (0.25 moles), and 8.24 g of Thiourea (0.10 moles) in 4050 ml of methanol. The solution was stirred at room temperature for 2.0 h.400.00 g of Neutral Alumina and 80.00 g of Sodium bicarbonate was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes, filtered and evaporated under atmospheric pressure at 60-65 °C to get a light green liquid. Dichloromethane (700.00 ml) was added to the green liquid, and the dichloromethane solution was washed with DM water (810 ml). The aqueous layer was re- extracted using 405 ml of dichloromethane. The combined dichloromethane layer was dried over sodium sulfate and filtered. The filtrate evaporated under atmospheric pressure at 40-45 °C. After complete distillation of dichloromethane, high vacuum (1 millibar) was applied for 15 minutes to obtain a greenliquid of dimethoxymethylcyclohexane (XII) (471 g, 80.00 %); purity (96.28 % by GC); Boiling point 97-98 °C (20 mm Hg). Example 13 Preparation of (Methoxymethylene)cyclohexane (XIII).

[0085] Pre-dried neutral Alumina (1.0 g) was added to Acetal of formula (XII) (20.0 g, 0.13 moles) and stirred for 30.00 hours at 180 °C. After 30.00 h, the sample showed 90.00 % of Vinyl ether, 0.70 % of Acetal, 1.58 % of cyclohexane carboxaldehyde. The reaction mass was then cooled to room temperature, the product was decanted from reaction flask to get vinyl ether (XIII) (8.8 g, 50 % (purity corrected)). Boiling point 168-172 °C. Example 14 Preparation of trans-2-methoxyspiro[2.5]octane-1-carboxylate (XIVA), Ethyl cis-2- methoxyspiro[2.5]octane-1-carboxylate (XIVB).

[0086] Ethyl diazoacetate (115.0 g, 1.00 moles) in Toluene (20 % Soln) was added drop wise to a slurry of (Methoxymethylene)cyclohexane of formula (XIII) (255.00 g, 2.02 moles) and freshly prepared Cu-bronze (16.0 g), at 100-105 °C was added over 7 hours and stirred for another one hour at the same temperature. The reaction mass was then cooled to room temperature and filtered. The filtrate comprised Toluene, unreacted vinyl ether, and cyclopropyl compound. Filtrate was distilled under atmospheric pressure to recover tolueneand unreacted vinyl ether (105.00 g). A brown color liquid residue mixture was obtained of Ethyl trans-2-methoxyspiro [2.5] octane-1-carboxylate (XIVA), and Ethyl cis-2- methoxyspiro[2.5]octane-1-carboxylate (XIVB) (cyclopropyl compound) (167.0g, 74.14 %); Purity (53.73+41.19) = 94.92 % by GC; Boiling point 125-140 °C (16 mm Hg). Example 15 Preparation of 1-Hydroxy-2-oxaspiro[4.5]decan-3-one (VII).

[0087] Hydrochloric acid (6 N, 670 ml, 4 vol) was added to (XIVA) and (XIVB) (167.00 g, 0.786 moles). The reaction mass was stirred at reflux temperature (100-105 °C) for 3 h. After 3 h, the reaction mass was cooled to room temperature, DM water was added (1670.00 ml, 10 vol) and the reaction mass was again heated to reflux temperature (100-105° C) for 5 h. After 5 h, the reaction mass was allowed to cool to room temperature. DCM (500 ml, 3 vol) was charged and stirred for 15 minutes, and the layers were separated. The aqueous layer was again extracted using dichloromethane (400.00 ml, 2.39 vol). The dichloromethane layers were combined, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to get crude lactol. Hexanes (300.00 ml, 1.80 vol) were added to the crude stirred at room temperature for 30 minutes. The solid (115.00 g) was filtered, purity: 96.12 % by HPLC. Cyclohexane (800.00 ml, 4.79 Vol) and Crude solid (115.00 g) were stirred at reflux temperature to get a clear solution. Charcoalization was done at the same temperature, filtered and the filtrate was cooled to 0-5 °C and maintained at the same temperature for one hour. Filtered the solid, washed using pre-chilled cyclohexane (100.00 ml), unloaded, dried under vacuum at 50-55° C to get pure lactol (VII) (105.00 g, 78.42 %), purity 99.28 % by HPLC. Melting point: 95-100° C. Example 16 Preparation of 1-[(Hydroxyimino)methyl] cyclohexaneacetic acid (XV).

[0088] Hydroxylamine hydrochloride solution (51.70 g, 0.74 moles, 157.50 ml DM water, 1.5 vol) was added to a mixture of Lactol (VII) (105.00 g, 0.62 moles), sodium carbonate (98.56 g, 0.93 moles), and methanol (157.5 ml, 1.5 Vol) at room temperature (25- 30 °C) and the mixture was maintained at room temperature for 2.0 hours. Methanol was evaporated under reduced pressure; water (315.00 ml, 3.0 vol) was added to the reaction mass and cooled to 05 °C. Hydrochloric acid (92.00 ml) was added dropwise to the reaction mass to adjust such that the pH was in the range of 1.0 to 2.0. The reaction mass was maintained at the same temperature for one hour, filtered and dried under reduced pressure to get 1-[(Hydroxyimino)methyl] cyclohexane acetic acid (XV) (110.00 g, 96.20 %), Purity 99.93 % by HPLC. %, Melting point: 120-125 °C. Example 17 Preparation of 1-[(Hydroxyimino) methyl] cyclohexaneacetic acid (XV).

[0089] Hydroxylamine hydrochloride solution (71.03 g, 1.02 mol, 217.5 ml DM water, 1.5 vol) was added to 1-Hydroxy-2-oxaspiro [4.5] decan-3-one (VII) (145.00 g, 0.85 mol), sodium carbonate (135.40 g, 1.27 mol), and methanol (217.5 ml, 1.5 vol) at room temperature (25-30 °C) and the mixture was maintained at room temperature for 2.0 hours. Methanol was evaporated under reduced pressure, water (435.00 ml, 3.0 vol) was added to the reaction mass and cooled to 0-5 °C. Hydrochloric acid (130.00 ml) was added drop wise to the reaction mass to adjust the pH to 1.0-2.0 The reaction mass was maintained at the same temperature for one hour, filtered and dried under reduced pressure to get 1 [(Hydroxyimino)methyl] cyclohexane acetic acid (XV) (148.92 g, 94.38 %), Purity 99.28 % by HPLC. Melting point: 120-125 °C.) Example 18 Preparation of 1-[(Hydroxyimino)methyl] cyclohexaneacetic acid (XV).

[0090] The clear solution of 1-Hydroxy-2-oxaspiro [4.5] decan-3-one (VII) (Lactol) (24 g, 1eq, 0.14 moles) in Methanol (36mL, 1.5 V) was pumped through pump-A at flow rate 5 mL / min and the solution of Hydroxylamine hydrochloride (11.7 g,1.2 eq, 0.16 moles) andsodium carbonate (23.9 g, 1.6 eq, 0.22 moles) in DM water (36 mL,1.5 vol) was pumped through pump-B at flow rate 5mL / min. Both the pump outlets were connected to 10 ml reactor and reaction was performed at 45°C with retention time 1 min. After reaction, mass was cooled to 25-30°C and methanol was removed by concentration under reduced pressure to yield crude residue. To the crude residue, water (72 ml, 3.0 vol) was added and cooled to 0-5° C. Hydrochloric acid (50.00 ml) was added dropwise to the reaction mass to adjust the pH to 1.0 to 2.0. The reaction mass was maintained at the same temperature for one hour, precipitated solid were collected by filtration and dried under reduced pressure to get 1- [(Hydroxyimino)methyl] cyclohexane acetic acid (XV) (24.7g, 93 %), Purity 91 pa % by HPLC. Melting point: 120°-125°C. Example 19 Preparation of Gabapentin (I).

[0091] 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV) (80.00 g, 0.43 moles) was dissolved in methanolic ammonia (44.00 ml), methanol (640.00 ml, 8.0 Vol) and hydrogenated at 60 °C, 30 kg / cm2 using Raney Nickel (28.0 g wet weight) for 6 h. The reaction mixture was filtered, and the filter bed was washed using methanol (80.00 ml); the filtrate was evaporated under vacuum at 40-45 °C to obtain crude (I). The crude and toluene (80.00 ml, 1.0 vol) were stirred at room temperature, filtered, and washed using Toluene (40.00 ml, 0.5 vol), crude weight: 62.00 g, 84.20 %. Purity by HPLC: Gabapentin: 90.00 % (w / w), Gabalactam: 0.31 % (w / w). Example 20 Preparation of Gabapentin (I).

[0092] 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV) (90.00 g, 0.48 mol) was dissolved in methanolic ammonia (49.00 ml) and methanol (7200.00 ml, 8.0 vol) and hydrogenated at 60° C, 30 kg / cm2 using Raney Nickel (28.0 g wet) for 6 hours. The reaction mixture was filtered, and the filter bed was washed using methanol (80.00 ml) when filtrateobtained was evaporated under vacuum at 40-45 °C to obtain crude (I). Crude and toluene (90.00 ml, 1.0 vol) was stirred at room temperature, filtered, and washed using Toluene (45.00 ml, 0.5 vol), crude weight: 67.00, 80.43 %. Purity by HPLC: Gabapentin: 83.30 % (w / w), Gabalactam: 0.14 % (w / w). Example 21 Preparation of Gabapentin (I).

[0093] A clear solution of 1-[(Hydroxyimino)methyl] cyclohexane acetic acid (XV) (5 gm, 1 eq, 0.026 moles) in mixture of methanol: methanolic ammonia (50 ml, 8:2V) was passed through the prepacked Raney nickel catalyst (80 gm, equal to 12 mL by considering 6.5 density of Raney Nickel) in catalytic reactor at liquid flow rate 1 ml / min and retention time 12min with 400 SCCM / min of hydrogen gas flow at pressure 20 bar and temperature 100°C±2°C. Collected reaction mass was cooled to room temperature and methanol was removed by concentration under reduced pressure to yield crude compound of Gabapentin. Above isolated crude was slurred in IPA (2V) at temperature 0-5°C for 1h. Precipitated solid was collected by filtration, dried under reduced pressure at 45-50°C to yield Gabapentin (I) (3.6 g, 72.2%) with purity 99 pa % by HPLC. Example 22 Purification of Gabapentin (I).

[0094] Gabapentin crude (70.00 g, 0.41 mol), methanol (258.00 ml, 3.68 vol), DM water (38.5 ml, 0.55 vol) were added to the crude and maintained at 60-65 °C for 30 minutes to get a clear solution. Charcoal (2.5 g) was added and maintained at the same temperature for 30 minutes. Isopropyl alcohol (370.00 ml, 5.28 vol) was added dropwise to the filtrate at room temperature and maintained at the same temperature for one hour, cooled to 0-5 °C and maintained at 0 -5 °C for one hour. The solid was filtered and washed using chilled Isopropyl alcohol (70.00 ml, 1.0 vol). Solid obtained was suck dried, unloaded, and dried under vacuum (1.0 millibar) at 60° C for 3.0 hours. The weight of the white solid pure gabapentin (56.5 g, 80.71 %), purity 99.60 % (w / w) by HPLC; Melting point-162-166 °C.

[0095] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this present disclosure and, without departing from the spirit and scope thereof, can make various changes and modifications of the present disclosure to adopt it to various usages and conditions.

Claims

CLAIMS:

1. A process for preparation of Gabapentin of formula (I),comprising: (a) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., hydroxylamine HCl) in a solvent and in presence of a base to obtain 1-[(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);(b) reducing the compound (XV) in a solvent and in a presence of alcoholic ammonia to provide Gabapentin (I).

2. The process according to claim 1, wherein the preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);comprises: (a) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(c) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);.

3. The process according to claim 1, wherein the preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);comprises: a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);(b) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(c) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(d) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);.

4. The process according to claim 1, wherein the preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);comprises: a) reducing Cyclohex-3-enecarbaldehyde (XI) to provide Cyclohexanecarboxaldehyde (VIII);b) acetalizatilising Cyclohexanecarboxaldehyde (VIII) in presence of a catalyst and in an alkanol solvent to provide dialkyloxymethylcyclohexane of formula (XII) .c) heating dialkyloxymethylcyclohexane compound of formula (XII) in presence of a catalyst to provide (alkyloxymethylene)cyclohexane of formula (XIII)d) reacting the (alkyloxymethylene)cyclohexane of formula (XIII) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2 alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2 alkyloxyspiro[2.5]octane- 1-carboxylate (XIVB);e) treating the mixture of alkyl trans-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVA) and alkyl cis-2-alkyloxyspiro[2.5]octane-1-carboxylate (XIVB) with an acid to obtain 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);.

5. The process according to claim 1, wherein, in (a) and (b), the solvent used is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, and 1,4 dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol; an aprotic solvent (e.g., esters) selected from ethyl acetate, acetonitrile, N,N- dimethyl formamide (DMF), N,N-dimethyl acetamide, and N-methylpyrrolidone (NMP); or an aromatic solvent selected from toluene and xylene; water; or a mixture thereof; in (a), the base is an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate, and caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate and potassium bicarbonate; or organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and in (b), the alcoholic solvent used in the preparation of alcoholic ammonia solution is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol.

6. The process according to claim 2, wherein,in (a), the base is an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate, and caesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate and potassium bicarbonate; and an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); in (b), the alkyl diazoacetate is selected from methyl diazoacetate, ethyl diazoacetate, n- propyl diazoacetate, isopropyl diazoacetate, n-butyl diazoacetate, isobutyl diazoacetate, sec butyl diazoacetate, tert-butyl diazoacetate, n-pentyl diazoacetate, n hexyl diazoacetate, and cyclohexyl diazoacetate; in step (b) the catalyst used for cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate and organometallic complexes of copper, rhodium; (e.g., Cuprous salts, rhodium (II) acetate and organometallic complexes of copper (I) and(II) and rhodium (II)) and in (c), the acid used is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, and boron trifluoride in ether.

7. The process according to claim 4, wherein, in (a) the reducing agent used is selected from Raney Nickel, Pd / C, zinc dust in presence of acid and sodium borohydride, hydrogen gas, and a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate; in (b) the alkanol solvent is selected from methanol, ethanol, n-propanol, n butanol, and n- hexanol; in (c) the acetal compound XII conversion to vinyl ether XIII is catalysed by an acid catalyst, a base catalyst, or neutral alumina; in (d) the alkyl diazoacetate is selected from methyl diazoacetate, ethyl diazoacetate, n- propyl diazoacetate, isopropyl diazoacetate, n-butyl diazoacetate, isobutyl diazoacetate, sec butyl diazoacetate, tert-butyl diazoacetate, n-pentyl diazoacetate, n hexyl diazoacetate, and cyclohexyl diazoacetate; in (d) the catalyst used for the cyclopropanation reaction is selected from copper, copper bronze, copper salts, rhodium acetate, organometallic complexes of copper, and rhodium; in (b), the catalyst used is a mixture of N-Chlorosuccinimide (NCS) and Thiourea; and in (e), the acid used is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluoride in ether.

8. The process as claimed in claim 1, wherein, the preparation of Gabapentin (I),comprises the steps of: a) treating Cyclohexanecarboxaldehyde (VIII) with acetic anhydride in presence of potassium carbonate to obtain Cyclohexylidenemethyl acetate (IX);b) reacting Cyclohexylidenemethyl acetate (IX) with Ethyl diazoacetate in presence of copper-bronze to obtain a mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1- carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1 carboxylate (XB);c) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with hydrochloric acid to obtain 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);d) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., preferably hydroxylamine HCl) in a solvent and in methanol and in presence of sodium carbonate to obtain 1 [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);e) reducing compound (XV) in methanol with methanolic ammonia to provide Gabapentin (I)..

9. The process according to claim 1 or claim 8, wherein the purification of Gabapentin (I) which is obtained from step (b) of claim 1 and step (e) of claim 8, comprises the steps of: (i) contacting Gabapentin in a mixture of water and an alcoholic solvent to form a mixture; (ii) optionally heating the mixture of step (a); (iii) adding isopropanol (IPA) to the mixture; (iv) cooling and filtering the obtained precipitate; (v) washing the precipitate with an alcoholic solvent; and (vi) drying the obtained solid of step (v) to obtain pure solid as Gabapentin (I).

10. The process according to claim 9, wherein the alcoholic solvent used in (i) and (v) is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol, and hexanol.

11. The process according to claim 1 or claim 8, wherein the compound of formula (I) obtained has a purity of at least 99% (e.g., 99.6) by HPLC.

12. A process for preparing Gabapentin (formula (I))comprising: formation ofprior to the formation of gabapentin, wherein R is an alkyl group.

13. A compound having the following structure:wherein R is an alkyl group selected from: methyl, ethyl, n-propyl, n-butyl, and n-hexyl.

14. A process for preparation of Gabapentin of formula (I) utilizing a flow chemistry process,comprising: (a) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine in a solvent and in presence of a base to obtain 1- [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);(b) reducing the compound (XV) in a solvent and in a presence of alcoholic ammonia to provide Gabapentin (I).

15. The process according to claim 14, wherein the preparation of 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);comprises: (a) treating Cyclohexanecarboxaldehyde (VIII) with an acetic anhydride in presence of a base to obtain Cyclohexylidenemethyl acetate (IX);(b) reacting the Cyclohexylidenemethyl acetate (IX) with an alkyl diazoacetate in presence of a catalyst to obtain mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane 1- carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB);(c) treating the mixture of alkyl trans-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XA) and alkyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid to obtain 1- hydroxy-2-oxaspiro[4.5]decan-3-one of formula (VII);.

16. A process for the preparation of gabapentin (I) utilizing a flow chemistry processcomprises the steps of: a) treating Cyclohexanecarboxaldehyde (VIII) with acetic anhydride in presence of potassium carbonate to obtain Cyclohexylidenemethyl acetate (IX);b) reacting Cyclohexylidenemethyl acetate (IX) with Ethyl diazoacetate in presence of catalyst to obtain a mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1 carboxylate (XB);c) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with hydrochloric acid to obtain 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII);d) reacting 1-hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII) with a hydroxylamine (e.g., preferably hydroxylamine HCl) in a solvent and in methanol and in presence of sodium carbonate to obtain 1 [(Hydroxyimino)methyl]cyclohexaneacetic acid (XV);e) reducing compound (XV) in methanol with methanolic ammonia to provide Gabapentin (I);.

17. The process according to claim 16, wherein the preparation of Cyclohexane carboxaldehyde (VIII) compressing, reducing Cyclohex-3-enecarbaldehyde (XI);.

18. A process for preparing gabapentin (I) using a flow chemistry process having industrial advantages, including ease of reaction, cost-effectiveness, and scalability for large-scale production, the method comprising: (a) cycling a reaction mass through a reactor multiple times under consistent conditions to achieve complete conversion of Cyclohex-3-enecarbaldehyde (XI) to cyclohexane-3- carboxaldehyde (VIII);(b)acetylating and isolating cyclohexane-3-carboxaldehyde (VIII) to produce cyclohexylidenemethylacetate (IX) as a colorless liquid with high purity through fractional distillation under reduced pressure; (c) reacting cyclohexylidenemethylacetate (IX) with alkyl diazoacetate in the presence of a catalyst under flow mode to synthesize (acetyloxy)spiro[2.5]octane-1-carboxylate (XA, XB), followed by purification via fractional distillation to separate starting materials; (d) treating the mixture of Ethyl trans-2-(acetoyloxy)spiro[2.5] octane-1-carboxylate (XA) and Ethyl cis-2-(acetoyloxy)spiro[2.5]octane-1-carboxylate (XB) with an acid by pumping the mixture with an acid at flow rate of 1ml / min into a reactor to obtain 1- hydroxy-2-oxaspiro [4.5]decan-3-one of formula (VII); (e) converting 1-hydroxy-2-oxaspiro[4.5]decan-3-one (VII) to gabapentin (I) through an intermediate, 1-[(hydroxyimino)methyl]cyclohexaneacetic acid (XV); wherein each reaction stage is optimized to ensure high efficiency, consistent yields, and suitability for industrial-scale production.

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