FIELD OF INVENTION

[0001] The present invention relates to a commercially viable and industrially advantageous process for the preparation of salts of piperidine carboxamides and pharmaceutically acceptable hydrate, solvate, enantiomer and stereoisomer thereof. The present invention specifically discloses process for the preparation of (E)-4-((l, 3 -bis (dodecanoy loxy) propan- 2-yl) oxy)-4-oxobut-2-enoate. l-butyl-N-(2, 6-dimethylphenyl) piperidine-2-carboxamide in high yield and purity.

BACKGROUND OF THE INVENTION

[0002] Amino amide compounds are a class of organic compounds currently used as local anesthetics. The clinically useful local anesthetics fall under two chemical groups such as amino amides (lidocaine, mepivacaine, prilocaine, ropivacaine, bupivacaine and etidocaine) and amino ester (procaine, chloroprocaine and tetracaine) compounds. The amino amide and amino esters compounds differ in terms of stability, metabolism and allergic potential. PABA (para amino benzoic acid) is an amino ester metabolite, producing allergic reactions in some patients. Amino amide compounds are not metabolized to PABA and they rarely cause allergic reactions and are preferably used as the local anesthetics.

[0003] Bupivacaine is one among the amino amide anesthetics which is currently in large demand for pain relief in patients with inflammation and ulceration of the oral mucous membranes (oral mucositis or OM), a serious complication following cancer treatment that prevents the completed treatment.

[0004] The present invention provides a process for preparation of salts of bupivacaine and levobupivacaine which is safe, cost effective, and industrially feasible. The conventional method of preparation includes highly cumbersome process, with high production cost, very long reaction hours, low yield and purity whereas the preparation process proposed by the present invention involves non-hazardous and easy to handle reagents, reduced reaction time and reduced synthesis steps. The process avoids then tedious and cumbersome procedures of the prior processes and is convenient to operate on a commercial scale producing high yield and purity.

SUMMARY OF THE INVENTION

[0005] In an embodiment, the present invention discloses a industrially feasible processes for the preparation of substantially pure compound of formula-I.

Formula I

IUPAC Name: (E)-4-((l, 3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate 1 -butyl - N-(2, 6-dimethylphenyl) piperidine-2-carboxamide.

Internal reference code: [CLX-SYN-G161-C11].

[0006] In another embodiment, the invention provides a process for preparing substantially pure (E)-4-((l, 3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate l-butyl-N-(2, 6- dimethylphenyl)piperidine-2-carboxamide of the formula-I or a pharmaceutically acceptable hydrate, solvate, enantiomer and stereoisomer thereof, one embodiment of the process comprising the steps of: a) Stage- 1: Condensation of 1,3 dihydroxy acetone with lauroyl chloride in the presence of suitable solvent, base and a catalyst forming an intermediate of formula-II. Formula-II b) Stage-2: Reduction of the carbonyl group of the intermediate compound of the formula-II in the presence of suitable reducing reagents and solvents forming an intermediate compound of formula-III.

Formula-Ill c) Stage-3: Esterification of the intermediate compound of formula-III with maleic anhydride, in presence of suitable base and solvents thereby forming the intermediate compound of formula- IV.

Formula-IV

The formed intermediate compound of formula-IV, is subjected to isomerization in presence of suitable acid catalysts and solvents converting the cis isomer to the trans isomer of formula- V.

Formula- V d) Reaction of the intermediate compound of formula-V with bupivacaine free base, thereby forming bupivacaine salt of formula-I by deprotonation in presence of suitable solvent. The bupivacaine free base is prepared by converting the commercially available bupivacaine hydrochloride monohydrate into bupivacaine free base in the presence of a suitable base and a solvent at a pH range 9 to 10.

[0007] In an embodiment, the catalysts used in the condensation reaction is 4- dimethylaminopyridine and is about 0.2 to 2 molar equivalents, per molar equivalent of the compound of formula- II.

[0008] In an embodiment, the organic solvent used in the condensation reaction, is N,N- dimethylformamide.

[0009] In an embodiment, the base used in the condensation reaction, is trimethylamine and the purification solvent used is isopropanol.

[0010] In an embodiment, the reducing agents used in the reduction reaction, is sodium cyanoborohydride and the solvent used is tertrahydran.

[0011] In an embodiment, the purification solvent used in the reduction reaction, is acetonitrile.

[0012] In an embodiment, the solvent used in the esterification reaction, is dichloromethane and the base used in the esterification reaction, is triethylamine.

[0013] In an embodiment, the solvent used in the isomerization reaction, is ethyl acetate, and the acid catalyst used in the isomerization, is para toluene sulfonic acid monohydrate.

[0014] In an embodiment, the purification solvent used in the isomerization reaction, is n heptane and isopropanol.

[0015] In another embodiment, the solvent used in the slat formation step for conversation of the compound of formula V to compound of formula I is ethyl acetate.

[0016] In an embodiment, the solvent used in the preparation of the bupivacaine free base in is water and the o preferred base used in the preparation of the bupivacaine free base is sodium carbonate.

[0017] In some embodiments, the temperature used range from -50° C to about 150° C. [0018] In some embodiments, the purification time range from 10 minutes to 6 hours and the purification temperature range from 0° C to 90° C. [0019] In an embodiment, the salt formation reaction for conversation of the compound of formula V to compound of formula I is performed at temperature range of 35° C to 40° C and for time interval about 15 to 16 hours.

[0020] In another embodiment, the invention provides processes for the preparation of highly pure intermediate compounds formed in the stages.

[0021] In another embodiment, the invention provides processes for the preparation compound of formula-I (CLX-SYN-G161-C11) with high yield.

[0022] In another embodiment, the invention provides processes for the preparation of the bupivacaine salt of formula-I or compound of formula I (CLX-SYN-G161-C11) with high purity and free from conventional impurities.

[0023] Unless otherwise defined, 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 invention relates. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0024] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0025] The term as used herein “substantially pure” means a chemical purity equal to or greater than 99.8 %, and/or a total content of impurities less than or equal to 0.2%, and /or each individual impurity being present in an amount less than or equal to 0.1%, as determined using high performance liquid chromatography (HPLC).

[0026] The term as used herein “substantially removing” the solvent refers to at least 80%, specifically greater than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the solution or suspension.

[0027] The term as used herein “Condensation catalyst”, may refer to the catalyst that increases the rate of the condensation involved.

[0028] The term as used herein “Choice of catalyst”, may influence whether or not a particular product is formed selectively (where the possibility of more than one product exists) and thus the catalyst may be selected according to the product or products desired from the reaction. It is envisaged that, where appropriate, combination of two or more suitable catalysts could be used. However, the use of a single catalyst is preferred. Alternatively, or additionally, selectivity may be controlled by independently varying one or more of the temperature, pressure, flow rate (in the case of a continuous process) and concentrations of the reactants.

[0029] The term as used herein “anti-solvent” refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance.

[0030] The term as used herein purity is based on the "organic" purity of the compound. Purity does not include a measure of any amount of water, solvent, metal, inorganic salt, etc. In one aspect, the purity of desired compound is compared to the purity of the reference standard by comparing the area under the peak.

[0031] The term as used herein “isomerization reaction” refers to a chemical reaction involving the conversion of the molecule into its isomers in the present of suitable solvents.

[0032] The present invention provides a industrially feasible processes for preparing substantially pure form of (E)-4-((l, 3-bis (dodecanoyloxy) propan-2-yl) oxy)-4-oxobut-2- enoate.l-butyl-N-(2,6-dimethylphenyl) piperidine-2 carboxamide of formula-I (CLX-SYN- G161-C11) or a pharmaceutically acceptable hydrate, solvate, enantiomer and stereoisomer thereof. In an embodiment the process of preparation of the compound of formula I of the present invention comprises of following steps:

Staged (Condensation):

[0033] Condensation of 1,3 dihydroxy acetone with lauroyl chloride in the presence of suitable solvent, base and a catalyst forming an intermediate dodecanoic acid 3- dodecanoyloxy-2-oxo-propyl ester of formula-II, which is further purified in the presence of a suitable solvent forming highly pure compound.

[0034] In an embodiment the non-limiting examples of the suitable condensation catalysts for the reaction include but are not limited to 4-dimethylaminopyridine (DMAP), diisopropylamine (DIPEA), 2-pyridone, l,4-diazabicyclo[2.2.2]octane (DABCO), 1,8- diazabicylco [5.4.0]undec-7-ene(DBU), 6-lutidine, 4-pyrrolidinopyridine, 2-hydroxypyridine, tributylphosphine, 1 -methylimidazole, N-Hydroxysuccinimide (NHS) 1 -hydroxybenzotriazole (HOBt), aluminumchloride, ironchloride, galiumtrichloride, antimonypentachloride, zincchloride, stannouschloride, aluminumbromide, ironbromide, stannicchloride, galliumtribromide, hydrogenflouride, borontrifluoride, dimethylaluminium chloride, diethylaluminium chloride, cerium(III)chloride, indium(III)chloride, titanium (IV) chloride, trimethylsilyltrifluoromethane sulfonate, platinum, palladium, or rhodium in concentrated sulfuric acid, and the like. In a specific embodiment the condensation catalysts is preferably 4- dimethylaminopyridine (DMAP).

[0035] In an embodiment the amounts of the catalysts used in the reaction is about 0.2 to 2 molar equivalents, per molar equivalent of the compound of Formula-II.

[0036] In still another embodiment the non-limiting examples of the suitable bases in reactions include, but are not limited to organic bases such as organolithiums, grignard reagents, amines, trimethylamine (TEA), N-heterocyclic compounds, tetra alkylammonium compounds and phosphonium hydroxides, metal alkoxides and amides and metal silanoates such as n- butyllithium, sec -butyllithium, tert-butyllithium, hexyllithium, isopropyllithium, butylmagnesium chloride, isopropylmagnesium chloride, propylmagnesium chloride, secbutylmagnesium chloride, tert-butylmagnesium chloride, 2-tert-butyl-l,l,3,3- tetramethylguanidine, ethylmagnesium bromide, ethylmagnesium chloride, hexylmagnesiumchloride, isobutylmagnesiumchloride, 2,2,6,6-tetramethylpiperidine, 4- (dimethylamino)pyridine, N,N diisopropylethylamine N,N diisopropylmethylamine, diethylamine, morpholine, piperidine, N-methylpiperidine, N-methylmorpholine, (piperidinomethyl)polystyrene,4-(dimethylamino)pyridine, lithium tert-butoxide, barium tert- butoxide, magnesium di-tert-butoxide, magnesium methoxide, potassium ethoxide, sodium tert-butoxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide, trimethylphenyl ammonium hydroxide, tetrapropylammonium hydroxide, tetrahexylammonium hydroxide, sodiumtert-pentoxide, sodium ethoxide, sodiumtert- butoxide, potassiumtert-butoxide, lithium isopropoxide, lithium ethoxide, lithiumtert- butoxide, bariumtert-butoxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, sodiumbicarbonate, sodium methoxide and similar methoxides of lithium, potassium, calcium, magnesium and barium compounds. In a specific embodiment the base is preferably triethylamine (TEA).

[0037] In another embodiment the non-limiting examples of the solvents used in the reaction includes but are not limited to, polar aprotic solvents such as N,N-dimethyl formamide, N,N- dimethylacetamide dimethyl sulfoxide, and N-methylpyrrolidinone; ethereal solvents such tetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, dimethyl ether, diethylether, dibutylether, diisopopyl ether, methyltert butyl ether, di-tert-butyl ether, 1,4-dioxane and diethoxymethane, diethoxyethane; hydrocarbons such as benzene, toluene, hexanes, xylene and heptane; halogenated solvents such as dichloromethane, ethylene bromide, ethylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate, and other solvents such as acetonitrile, methyl vinyl ketone; and mixtures thereof. In a specific embodiment the solvent is preferably N,N- dimethylformamide (DMF).

[0038] In another embodiment the stage- 1 reaction may be performed at temperatures -50° C to about 150° C, preferably in the range from -25° C to about 100° C, and more preferably in the range of from 0° C. to 50° C.

[0039] In another embodiment the stage- 1 reaction may be performed at temperatures -50° C to about 150° C preferably in the range from -25° C to about 100° C and more preferably in the range of from 0° C to 50° C. [0040] In another embodiment the stage- 1 reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 20 hours, or longer, as required for the reaction completion.

[0041] In another embodiment the non-limiting examples of the purification solvents include, but are not limited to n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, methanol, ethanol, n-propanol, 2-ethylhexanol isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, mesityl oxide, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, trichloroethylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof. In an embodiment, the purification solvents is preferably isopropanol.

[0042] In another embodiment stage- 1 purification reaction is carried out at a temperature of -20° C to the reflux temperature of the solvent used for at least 10 minutes, specifically at a temperature of about 0° C to about 50° C for about 20 minutes to about 6 hours, and more specifically at a temperature of about 0° C to about 65° C for about 1 hour to about 4 hours and further more specifically at a temperature of about 0° C to about 90° C for about 30 minutes to 1 hour. The process of crystallization of the pure compound is initiated after cooling the reaction mixture to -20° C to R. T.

Stage.2 (Reduction):

[0043] Reduction of the carbonyl group of the intermediate compound of the formula-II in the presence of suitable reducing reagents and solvents forming an intermediate compound dodecanoic acid 3-dodecanoyloxy-2-hydroxy-propyl ester of formula-III which is further purified in the presence of a suitable solvent forming highly pure compound. [0044] In another embodiment the non-limiting examples of the reducing agents used in the stage-2 include but are not limited to hydride reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), lithium triethylborohydride, lithium tri-tert- butoxyaluminum hydride, zinc borohydride, sodium borohydride-cerium chloride (luchereagent), lithium tri-sec-butylborodeuteride, sodium bis(2-methoxyethoxy) aluminum hydride (vitride or red aluminium) thereof, In one embodiment, reducing agent is preferably sodium cyanoborohydride.

[0045] The non-limiting examples of the organic solvents used in the stage-2 reaction is as described in the preceding paragraphs. In specific embodiment, the organic solvent is preferably tetrahydrofuran.

[0046] The non-limiting examples of the purification solvents used in the stage-2 reaction is as described in the preceding paragraphs preferably acetonitrile.

[0047] In another embodiment the stage-2 reaction may be performed at temperatures -50° C to about 150° C, preferably in the range of from -25° C to about 100° C, and more preferably in the range of from 0° C to 50° C.

[0048] In another embodiment the stage-2 reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 20 hours, or longer, as required for the reaction completion.

[0049] In another embodiment stage-2 purification reaction is carried out at a temperature of -20° C to the reflux temperature of the solvent used for at least 10 minutes, specifically at a temperature of about 0° C to about 50° C for about 20 minutes to about 6 hours, and more specifically at a temperature of about 0° C to about 65° C for about 1 hour to about 4 hours and further more specifically at a temperature of about 0° C to about 90° C for about 30 minutes to 1 hour. The process of crystallization of the pure compound is initiated after cooling the reaction mixture to -20° C to R. T.

Stage.3 (Esterification & Isomerization)

[0050] Esterification of the intermediate compound of formula-III with maleic anhydride, in presence of suitable base, solvents thereby forming the intermediate compound of formula-IV. The formed intermediate compound of formula-IV, is subjected to isomerization in presence of thiourea, suitable acid catalysts and solvents converting the cis isomer to the trans isomer (E)-But-2-enedioic acid mono-(2-dodecanoyloxy- 1 -dodecanoyloxymethyl-ethyl) ester of formula-V. The formed intermediate compound V is subjected to purification to yield highly pure compound.

[0051] The non-limiting examples of the organic solvents used in the stage-3 reaction is as described in the preceding paragraphs preferably dichloromethane.

[0052] In another embodiment the non-limiting examples of the organic solvents used in the stage-3 reaction is as defined in preceding paragraphs preferably ethyl acetate.

[0053] The non-limiting examples of the bases used in the stage-3 reaction is as described in the preceding paragraphs. In one embodiment, base is preferably triethylamine.

[0054] In another embodiment the stage-3 reaction may be performed at temperatures -50° C to about 150° C, preferably in the range of from -25° C to about 100° C, and more preferably in the range of from 0° C to 50° C.

[0055] In another embodiment the stage-3 reaction may be performed at temperatures -50° C to about 150° C, preferably in the range of from -25° C to about 100° C, and more preferably in the range of from 0° C to 80° C, followed by the cooling of the reaction temperature to-20° C to 25° C. [0056] In another embodiment the stage-3 reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 20 hours, or longer, as required for the reaction completion.

[0057] The non-limiting examples of the acid catalysts used in the stage-3 isomerization include but are not limited to para toluene sulfonic acid, sodium para toluene sulfonate, methyl para toluene sulfonate, methanesulfonic acid, sodium methanesulfonate, ethanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid sodium salt, benzenethionosulfonic acid sodium salt, ammonium xylene sulfonate, hydrofluoric acid, ortho-phosphoric acid, polyphosphoric acid (phosphorous pentoxide and ortho-phosphoric acid), Eaton’s reagent (phosphorous pentoxide and methanesulfonic acid), polystyrene sulfonate, heteropoly acids, zeolites and mixtures thereof. In one embodiment, acid catalysts is preferably para toluene sulfonic acid monohydrate.

[0058] The non-limiting examples of the purification solvents used in the stage-3 reaction is as described in the preceding paragraphs. In one embodiment, solvent is preferably n-heptane. [0059] In another embodiment the non-limiting examples of the purification solvents used in the stage-3 reaction is as described in the preceding paragraphs. In one embodiment, purification solvents is preferably isopropanol.

[0060] In another embodiment stage-3 purification reaction is carried out at a temperature of -20° C to the reflux temperature of the solvent used for at least 10 minutes, specifically at a temperature of about 0° C to about 50° C for about 20 minutes to about 6 hours, and more specifically at a temperature of about 0° C to about 65° C for about 1 hour to about 4 hours and further more specifically at a temperature of about 0° C to about 90° C for about 30 minutes to 1 hour. The process of crystallization of the pure compound is initiated after cooling the reaction mixture to -20° C to R. T.

Stage-4(Salt formation):

[0061] Reaction of the intermediate compound V with the bupivacaine free base in the presence of suitable solvents yielding the final compound I, which is further subjected to purification thereby yielding highly pure compound I. The bupivacaine free base used in the aforementioned reaction is produced by converting the commercially available bupivacaine hydrochloride monohydrate into free base upon reaction with suitable base and solvents.

[0062] The non-limiting examples of the organic solvents used in the stage-4 reaction is as described in the preceding paragraphs. In one embodiment, the solvent is preferably water.

[0063] In another embodiment, organic solvent is preferably ethyl acetate.

[0064] The non-limiting examples of the bases used in the stage-4 reaction is as described in the preceding paragraphs. In one embodiment, the base is preferably sodium carbonate.

[0065] In another embodiment the stage-4 reaction may be performed at temperatures -50° C to about 150° C, preferably in the range of from -25° C to about 100° C, and more preferably in the range of from 0° C to 50° C.

[0066] In another embodiment the stage-4 reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 20 hours, or longer, as required for the reaction completion.

[0067] In another embodiment stage-4 purification reaction is carried out at a temperature of -20° C to the reflux temperature of the solvent used for at least 10 minutes, specifically at a temperature of about 0° C to about 50° C for about 20 minutes to about 6 hours, and more specifically at a temperature of about 0° C to about 65° C for about 1 hour to about 4 hours and further more specifically at a temperature of about 0° C to about 90° C for about 30 minutes to 1 hour. The process of crystallization of the pure compound is initiated after cooling the reaction mixture to -20° C to R. T.

[0068] The detailed process is represented in the Scheme-I:

[0069] In one embodiment, aforementioned process involves drying, which is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as 35° C to about 80° C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperature and pressure are chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dyer, a flash dryer or suck drying, vacuum dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

[0070] The non-limiting examples of the reagents used for adjusting the pH of the chemical reactions in present invention includes but are not limited to bases such as sodium carbonate, potassium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide and acids such as phosphoric acid, hydrochloric acid, nitric acid, carbon dioxide , sulfuric acid and citric acid. [0071] In one embodiment the reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. ’H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC)

[0072] In one embodiment, the present invention relates to the desired final compound of formula-I (CLX-SYN-G161-C11) having a purity greater than about 98%. In one embodiment, the purity is greater than about 98.5%. In one embodiment, the purity is greater than about 99.0%. In one embodiment, the purity is greater than about 99.5. In one embodiment, the purity is determined by HPLC.

[0073] The above described process for the preparation of compound of Formula-I (CLX- SYN-G161-C11) is resulting in cost-effective and reproducible process on industrial scale. The process of present invention provides higher overall yield and purity.

[0074] Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the invention in any manner.

METHODS OF MAKING

[0075] The synthetic pathways useful for making compound of Formula-I are set forth in the not limiting to the example below.

Stage 1: [0076] Preparation of dodecanoic acid 3-dodecanoyloxy-2-oxo-propyl ester (Stage-1 intermediate):

[0077] Charge di methylformamide and 1,3-dihydroxy acetone (150 g) and stir for 10-15 min at 25-30° C to dissolve completely, then add triethylamine (928 ml) followed by 4- dimethylaminopyridine (40.6 g) at 25-30 °C and stir for 5-10 min. Cool the reaction mixture to 0-5°C,add lauroyl chloride (962 ml) dropwise, keeping the internal temperature below 10 °C. Stir the reaction mixture for 15-20 min at 5 to 10 °C. Allow the reaction mixture to stir at 25-30 °C for 14-16 h. Pour the contents of the reaction mixture to ice cold water. Adjust the pH to 3-4 by adding citric acid. Stir the mixture for Ih.Filter the solid, wash the filter cake with water. Suck dry the solid for 4-5 h. Dry the crude Stage-01 material in hot air oven at 40-45 °C for overnight. The crude is purified by the addition of isopropanol with stirring at 25-30 °C for 15-20 min followed by heating the mixture to 80-85 °C. Then, the reaction mixture is cooled to room temperature. The solid is filtered and dried in hot air oven at 40-45 °C for 4-5 h; (Yield = 67.4%; Purity = 94.75%).

Stage 2:

[0078] Preparation of dodecanoic acid 3-dodecanoyloxy-2-hydroxy-propyl ester (Stage-2 intermediate):

[0079] Charge THF (4.0 1) into RBF at 25-30° C. To this add Stage- 1 intermediate (400 g). Stir for 5-10 min. Cool the reaction mixture to 0-5° C. Charge acetic acid (75.4 ml) at 0-5° C and stir for 5 min. Charge sodium cyanoborohydride (82.92 g) portion wise slowly at 0-5° C over a period of 40 min. Stir for 15 min at 0-5° C . Allow the reaction mixture to stir at 25-30° C for 5-6 h. Evaporate the solvent under vacuum, Stir the crude mass in DM water (4.0 L) at 25-30° C for 2 h. Filter the solid, wash the filter cake with water. Dry the crude stage-02 in hot air oven at 40-45 °C for 4-5 h. The crude is purified by the addition of acetonitrile and stirring at 25-30 °C for 15-20 min followed by heating the mixture to 80-85 °C .Then reaction is gradually cooled to room temperature. The obtained solid is filtered and dried in hot air oven at 40-45 °C for 4-5 h; (Yield = 80.15% )

Stage 3:

[0080] Preparation of (E)-but-2-enedioic acid mono-(2-dodecanoyloxy-l- dodecanoyloxymethyl-ethyl) ester (Stage-3 intermediate of formula V)

[0081] Charge dichloromethane (3.5 1) and Stage-2 intermediate (350g) while stirring at 25- 30 °C for 10-15 min. Charge triethylamine (320 ml) dropwise at 25-30° C and for 5 min. Then add maleic anhydride (113 g) gradually portion wise at 25-30° C over a period of 40 min and stir the reaction mixture at 25-30° C for 15-16 h. Dilute the reaction mass with dichloromethane (1.0 L). Wash the dichloromethane layer with IN HC1 and evaporate the dichloromethane under reduced pressure at 40-45 °C. To the 300g of stage-3 intermediate is added ethyl acetate and stirred for 10 min at 25-30 °C. Charge thiourea (38.5 g) at 25-30°C and stir for 5 min. Then PTSA monohydrate (14.5 g) is added at 25-30°C and stirred for 5 min. Heat the reaction mixture to reflux at 75-78 °C for 16h, followed by cooling to 25-30 °C. DM water is added, and the organic layer is separated and evaporated under reduced pressure. The crude is purified by the addition of n-heptane and stirring at 25-30 °C for 15-30 min followed by heating the mixture to 80-85 °C Then the reaction mixture is subjected to cooling to room temperature. Filter the solid and suck dry for 2-3 h. Re purification is carried out by the addition of isopropyl alcohol and stirring at 25-30 °C for 15-20 min followed by heating the mixture to 80-85 °C for 1 hour and subsequent cooling to room temperature. The obtained solid is filtered and collected. Suck dry the solid for 2-3 h followed by drying in hot air oven at 40-45 °C for 4-5 h. (Yield = 64.7 %; Purity = 99.07%)

Stage 4:

Mol. Wt: 342.91 Mol. Wt: 288.44

Bupivacaine hydrochloride Bupivacaine free base monohydrate

[0082] Preparation of bupivacaine free base

[0083] Charge DM water (2000ml) into a RB flask with bupivacaine hydrochloride monohydrate (200 g) and stir for 5-10 min to dissolve completely. Charge aq NazCCh solution (123 g in 400 ml water) dropwise at 10-15 °C. Stir the reaction mass at 25-30 °C for 30 min. The pH of the solution is maintained at the range of pH 9-10. Filter the solid and wash the filter cake with water. Suck dry for 2 h. Dry the solid at 40-45° C for 4-5 h (Yield = 91.8%, Purity = 99.93%).

Stage 5:

[0084] Preparation of (E)-4-((l, 3-bis (dodecanoyloxy) propan-2-yl)oxy)-4-oxobut-2- enoate. l-butyl-N-(2, 6-dimethylphenyl)piperidine-2-carboxamide [CLX-SYN-G161-C11 (formula-I)]: [0085] Charge Ethyl acetate (2000 ml) into a RB Flask and add stage-3 intermediate (200gm) at 25-30° C and stir for 10 min. Charge bupivacaine free base (104 g) at 25-30°C and continue stirring at 25-30° C for 15-16 h. Filter the reaction mass through 0.2 p filter paper and rinse the reaction vessel/RB with ethyl acetate. Evaporate ethyl acetate under reduced pressure at 35-40 °C. Final product (CEX-SYN-G161-C11) is collected, (Yield = 98.6%).

EQUIVALENTS

The present disclosure provides among other things the processes for the preparation of salts of bupivacaine dilauryl glyceryl fumarate (CEX-SYN-G161-C11) and their pharmaceutically acceptable hydrates, solvates, enantiomers and stereoisomers thereof. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed processes and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.