WO2023086696A2

WO2023086696A2 - Apparatus and methods for continuous flow synthesis of cisatracurium

Info

Publication number: WO2023086696A2
Application number: PCT/US2022/076246
Authority: WO
Inventors: Brenden Herrera; Jonathan Samuel; Josef Maier
Original assignee: ODH IP Corp.
Priority date: 2021-11-10
Filing date: 2022-09-09
Publication date: 2023-05-19
Also published as: WO2023086696A3

Abstract

Disclosed herein are novel approaches for the on-demand continuous flow synthesis of cisatracurium. The synthesis route involves one or more steps wherein reactants are flown through a reactor. The resulting product is transferred to a filter directly in a continuous system.

Description

APPARATUS AND METHODS FOR CONTINUOUS FLOW SYNTHESIS OF

CISATRACURIUM

GOVERNMENTAL RIGHTS

[ 1 ] This invention was made with government support under DARPA Cooperative Award

# HR-0011-16-2-0029 awarded by the Defense Advanced Research Projects Agency of the Department of Defense. The government has certain rights in the invention.

CROSS REFERENCE TO RELATED APPLICATION

[2] This application claims priority from U.S. Provisional Application No. 63/278,027, filed November 10, 2021, and is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[3] Disclosed herein is a method for on-demand continuous flow synthesis of cisatracurium besylate from 3,4-dimethoxyphenylacetic acid (DMPA), and other intermediate chemical molecules which can be adapted to a portable system.

BACKGROUND

[4] Cisatracurium besylate (Compound XII) has the chemical name (1R, 1 'R,2R,2'R)-2,2'-

[l,5-pentanediylbis[oxy(3-oxo-3, l-propanediyl)]]bis[l-[(3, 4-dimethoxyphenyl)methyl]-l, 2,3,4- tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate and is represented by the structure below:

XII

[5] Cisatracurium besylate is a nondepolarizing neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU). Cisatracurium besylate possesses an activity that is superior to atracurium besylate, with significantly fewer side effects.

[6] Cisatracurium besylate slowly loses potency with time at a rate of approximately 5% per year under refrigeration (5° C ). Cisatracurium besylate should be refrigerated at 2° to 8° C. (36° to 46° F.) in the carton to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C.

[7] Current methods for the synthesis of cisatracurium besylate are batch type processes which have various issues including stability, efficiency, and physical limitations by production equipment. Thus, there is a need to develop improved synthetic approaches to produce significant quantities of cisatracurium besylate in an on-demand and continuous process to overcome the above issues.

SUMMARY OF THE INVENTION

[8] This patent disclosure provides an efficient on-demand and continuous process approach for cisatracurium production. A target compound and its synthetic intermediates can be readily prepared with the method disclosed herein.

[9] The compound of formula XII can be prepared according to the following steps: reacting a compound of formula XI and 1,5-pentanediol in the presence of benzenesulfonic acid in a first organic solvent, wherein the first solvent is capable of dissolving XI, benzenesulfonic acid and 1,5-pentanediol; obtaining a resulting mixture containing the compound of formula XII; and selectively removing the compound of formula XI with a two-solvent system. The resulting solution, containing compound of formula XII is then isolated by reverse anti-solvent addition, lyophilization or spray drying to afford pure cisatracurium besylate as an amorphous solid.

[10] In some embodiments, the first organic solvent is selected from di chloromethane (DCM), tetrahydrofuran (THF), acetone, dimethylformamide (DMF), dimethylacetamide (DMA), 1,2-dichloroethane (DCE), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), chloroform, acetonitrile (ACN), and any mixture thereof.

[11] In some embodiments, the second organic solvent is selected from diethyl ether, diisopropyl ether, tert -butyl methyl ether, toluene, xylenes, 2-methyltetrahydrofuran, and any mixture thereof.

[12] In some embodiments, the reaction is allowed to proceed at a temperature ranging from about 50 °C to about 100 °C. In some embodiments, the reaction continues for about 5 to about 90 minutes.

[13] In some embodiments, the reaction is allowed to proceed in the presence of a desiccant, e.g., calcium sulfate or molecular sieves.

[14] In some embodiments, the synthesis of the compound of formula XII is carried out using a continuous flow process or manner.

[15] The compound of formula XI can be prepared according to the following steps: flowing a mixture of a compound of formula X and hydrogen gas through a first reactor to form the compound of formula XI; adding an antisolvent; and transferring the suspension of formula XI to a filter. Filtration and subsequent washing with an antisolvent affords compound of formula XI.

X

[16] In some embodiments, the reactor and the filter are connected for transferring the compound XI. In some embodiments, the method includes precipitating out and washing the transferred compound XI in the filter.

[17] In some embodiments, the synthesis of the compound of formula XI is carried out in a solution of dichloromethane. [18] In some embodiments, the synthesized compound of formula XI is precipitated with diethylether.

[19] In some embodiments, the synthesis of compound of formula XI is carried out using a continuous flow process or manner.

[20] In some embodiments, the compound of formula X can be prepared according to the following steps: neutralizing a compound of formula IX with a base; flowing a mixture of the neutralized compound and a methylating agent through a reactor to form the compound of formula X; and enriching in a filter the compound X over the undesired diastereomer.

[21] In some embodiments, the second reactor and the second filter are connected for transferring the compound of formula X. In some embodiments, the mixture of the neutralized compound and the methylating agent is dissolved in a solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, tetrahydrofuran, DMSO, DMF, and any mixture thereof.

[22] In some embodiments, the (1R, 2R) diastereomer of compound of formula X is separated from the (1R, 2S) diastereomer in a module comprising a filter unit, a washer unit, and a dryer unit.

[23] In some embodiments, the synthesis of the compound of formula X is carried out using a continuous flow process or manner.

[24] In some embodiments, the compound of formula IX can be prepared according to the following steps: lowing a mixture of a compound of formula Villa and an acrylate through a reactor to form an acrylated compound via an acrylation reaction, wherein the acrylate is of the formula CH2=CHCOY, wherein Y is OR¹ or NR²R³, R¹ is alkyl, aryl or heteroaryl, and R² and R³ are the same or different and each is independently selected from hydrogen, Ci-6 alkyl, aryl and heteroaryl; mixing the acrylated compound with oxalic acid form the compound of Formula IX in a filter.

Villa IX

[25] In some embodiments, the method includes, prior to mixing the acrylated compound with oxalic acid, quenching the acrylation reaction. In some embodiments, the mixture of the compound Villa and the acrylate further comprises a solvent selected from toluene, xylenes, benzene, ethyl acetate, di chloromethane, chloroform, acetonitrile, and any mixture thereof, and wherein the acrylate is benzyl acrylate.

[26] In some embodiments, the synthesis of the compound of formula X is carried out using a continuous flow process or manner.

[27] In some embodiments, the synthesis of the compound of formula X is carried out using a plug flow reactor. The compound of formula Villa can be prepared according to the following steps: flowing a mixture of the compound of formula V and phosphorous oxychloride in a reactor to form the compound of formula VI; neutralizing the compound of formula VI with a base followed by mixing and phase separation and collection of the organic layer; diluting the collected compound of formula VI with polar organic solvent and a reducing agent in the presence of a base and reducing the compound of formula VI to form the racemic compound of formula VII; mixing the compound of formula VII with a S-arylpropionic acid to form the compound of formula VIII; isolating the compound of formula VIII in a filter; and neutralizing it with a base to form the compound Villa.

[28] The compound of formula V can be prepared according to the following steps: flowing a mixture of a compound of formula I and a compound of formula II through a reactor to form the compound of formula III (in a continuous flow system to form 3,4-dimethoxyphenylacetyl chloride (III)); and flowing a mixture of the compound of formula III and a compound of formula IV in the presence of a base in a reactor to form the compound V.

[29] In some embodiments, the compound V is precipitated, and the resulting solid is slurried in a mixture of dichloromethane/isopropanol/pentane to afford pure V. In some embodiments, the fourth plug flow reactor is connected to the fifth plug flow reactor and the fifth plug flow reactor is connected to the fifth filter.

[30] In some embodiments, the synthesis of one or more of the above compounds can be carried out in a POD unit apparatus and methods of use of the apparatus of the present invention comprise a plurality of chemical steps using the various modules. These steps may include, but are not limited to chemical, photochemical, and electrochemical reactions (using PFRs), distillations, separations, pervaporation, evaporation, thin-film distillation, etc. The crude material is then purified using a series of unit operations within the apparatus, including but not limited to precipitation, filtration, washing, drying, dissolution, crystallization, chromatographic separation, evaporation.

DESCRIPTION OF THE DRAWINGS

[31] Figure 1 shows an example of a route for the synthesis of cisatracurium besylate.

DETAILED DESCRIPTION

[32] This patent specification discloses a new on-demand, continuous approach to the synthesis of cisatracurium. In comparison with conventional methods, this approach is efficient and portable with reduced environmental impact.

[33] While the following text may reference or exemplify specific embodiments of a reaction, a reagent, a device or a component thereof, it is not intended to limit the scope of the reaction, the reagent, the device, or the component thereof to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of scientific and practical considerations, such as change of reaction conditions and replacement of reagents.

[34] The articles "a" and "an" as used herein refer to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.

[35] The term "alkyl" refers to a hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched. The term "Ci-6 alkyl" refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples include groups such as CH3, (CH2)2CH3, CH2CH(CH3)CH3, and the like. Similarly, the term "C2-5 alkyl" refers to alkyl groups having 2, 3, 4 or 5 carbon atoms.

[36] The term “aryl” and “heteroaryl,” as used herein, means a monocyclic or polycyclic aromatic group (e.g., phenyl or naphthyl) or a heteroaromatic ring containing 0-3 heteroatoms selected from O, N or S. Unless otherwise indicated, the aryl and the heteroaryl groups can be un-substituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, Ci-ealkyl, OCF3, NO2, CN and OC1-6 alkyl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.

[37] The term “halogen” refers to F, Cl, Br or I. [38] This patent document provides an on-demand, continuous method for the efficient synthesis of cisatracurium besylate. The synthesis in some embodiments employs a continuous flow production method. As a result, the production is more efficient and less time-consuming than many conventional approaches. Meanwhile, the production can be accomplished in a portable and automated device, where different components are inter-connected and operated via a computerized system.

[39] As shown in Figure 1, which illustrates an example of an embodiment for synthesis of cisatracurium besylate, the product and intermediates can be readily prepared and isolated. Some steps of the process can take place in a device having either separate components that function as a reactor, a filter, a purifier, or a dryer. In some embodiments, the device can have components that have combined functions, e.g., filter and washer, or filter, washer and dryer for example. The device used for synthesis is suitable for the synthesis of a target product as well as intermediates leading to the product.

[40] The synthesis of compound XII generally involves reacting compound XI and 1,5- pentanediol in the presence of benzenesulfonic acid in an organic solvent, followed by transferring the resulting mixture containing compound XI from a reactor to a filter or collector and isolating the product. In some embodiments, the reactor can be a stirred tank reactor (STR), a continuous stirred tank reactor (CSTR), or a plug flow reactor (PFR).

[41] In some embodiments, the reactor is connected to the filter via a tube or pipe so that the mixture can be conveniently transferred. As stated above, in some embodiments, the reaction can proceed in a component of a device providing the function of filtration, the component may have combined functions so that, for example, the filter component can also serve as a washer component and dryer component. In some embodiments, the collector or filter component can also allow for functions such as a reaction (e.g., salt formation) and recrystallization. For instance, a collector component may be a filter defined by a top, a bottom and side wall connecting the top and the bottom. The top has one or more openings or ports for liquid to fill into the filter. The openings can be pores in porous materials such as porous Hastelloy filter plates. The bottom has one or more openings or a permeable membrane for filtering out the liquid. The size of the openings or the permeability of the membrane at the bottom is selected based on the nature of the product or intermediate and the impurity or side products to be removed. The flow of liquid through the bottom can be controlled by vacuum or pressure or a removable gate. A mixture of reagents or solvents filled into the filter can be stirred or agitated to promote further reaction, extraction, or isolation before the liquid is released from the bottom. Any solid remaining in the filter can be dried under vacuum, air pressure (e.g., nitrogen or argon gas), or heating.

[42] The organic solvent for the reaction between compound XI and 1,5-pentanediol is capable of dissolving the reactants and benzenesulfonic acid. Non-limiting examples of the solvent include dichloromethane, tetrahydrofuran (THF), acetone, dimethylformamide, dimethylacetamide, 1,2-di chloroethane, dimethyl sulfoxide (DMSO), ethyl acetate, di chloromethane, chloroform, acetonitrile, and any mixture thereof. In some embodiments, the solvent is dichloromethane.

[43] The product mixture transferred to the filter is further mixed with a second organic solvent to promote precipitation of the product solid for compound XII. If necessary, the transferred liquid can be concentrated to remove some solvent. Subsequent addition of the second solvent, optionally with heating, can lead to recrystallization of compound XII. Non-limiting examples of the second solvent include diethyl ether, diisopropyl ether, tert -butyl methyl ether, toluene, xylenes, Cs- 12 saturated hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, and the like, and any mixture thereof. In some embodiments, the second solvent is diethyl ether. The dual solvent approach can also be applied to the precipitation or recrystallization of other intermediates disclosed herein.

[44] The reaction between compound XI and 1,5-pentanediol may proceed at a temperature ranging from about 50 °C to about 150 °C, from about 60 °C to about 120 °C, or from about 70 °C to about 100 °C. Non-limiting examples of the reaction temperature include about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, and about 120 °C. The reaction time may range from about 5 to about 90 minutes, from about 5 to about 70 minutes, from about 5 to about 60 minutes, or from about 10 to about 50 minutes.

[45] In alternative embodiments, the process for producing cisatracurium salt, e.g., cisatracurium besylate, includes coupling compound XI (e.g., about 2 equivalents) with 1,5- pentanediol (HO(CH2)5OH), to produce cisatracurium salt, e.g., cisatracurium besylate, and optionally isolating the cisatracurium salt. The coupling process can be carried out using any suitable method. In some embodiments, the coupling process includes activating the carboxylic acid of compound XI and reacting the activated compound with 1,5 -pentanediol. Compound XI can be activated using any suitable method, e.g., by converting compound XI into the corresponding acid halide (e.g., acid chloride), activated ester, or by any other suitable methods, including methods that can be used for esterifying carboxylic acids.

[46] Compound XI can be prepared by flowing a mixture of compound Formula X and an acid through a flow reactor, which is filled with dichloromethane or similar solvent, such as, for example, chloroform, or mixtures of propan-2-one/cyclopentane, and ethyl acetate/ethanol, ethyl acetate/heptane, ethyl acetate, MTBE, toluene, 2-MeTHF.

[47] The flowing of the mixture includes retaining the mixture inside the reactor for a suitable amount of time if needed and moving the mixing from one end to the other end of the reactor. In some embodiments, the time for retaining the mixture can be adjusted depending on the nature of the reaction and the reactivity of the reactants. The moving of the mixture can be driven by gravity, pressure, vacuum, and any suitable force.

X

[48] In some embodiments, the flow reactor and the filter are connected for example via a tubing or pipe so that the product mixture is directly transferred to the filter for purification and isolation. Such as continuous transfer without isolation of the product mixture can be operated via a computerized program and improve the efficiency of the manufacturing with minimum chemical exposure to humans and environment. The purification may include compound precipitation and washing.

[49] Non-limiting examples of the acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid (TFA), methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Amberlyst® 15 hydrogen form, Amberlite® IR120 hydrogen form or Amberjet® 1200 hydrogen form. Preferred organic acids (including acidic ion exchange resins) are TFA, and Amberlyst® 15 hydrogen form. In some embodiments, the acid is benzenesulfonic acid.

[50] The solvent in the mixture for the preparation of Compound XI can be selected from for example acetone, methyl ethyl ketone, dichloromethane, chloroform, 1,2-di chloroethane, and mixtures thereof. In some embodiments, the solvent is di chloromethane.

[51] After the mixture containing compound XI is transferred to a filter, a different solvent is added to precipitate out compound XI. Non-limiting examples include diethylether, isopropyl ether, tert-butyl methyl ether, toluene, xylenes, and mixtures thereof. In some embodiments, the second solvent for promoting precipitation is diethyl ether.

[52] Compound X can be prepared by neutralizing compound IX with a base followed by flowing a mixture of the neutralized compound and a methylating agent through a flow reactor to form the compound X. The flow reactor is as described above. The product mixture can then be transferred to a filter, where a different solvent is added to precipitate out compound X. In some embodiments, the flow reactor and the filter are connected so that the product mixture is directly transferred to the filter for purification and isolation. The purification may include compound precipitation and washing.

IX

[53] Non-limiting examples of the base include ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or any suitable combination thereof. In some embodiments, the base is sodium hydroxide. The neutralized compound can be extracted with for example toluene, xylenes, ethyl acetate, dichloromethane, chloroform, or a mixture thereof. [54] The methylating agent can be dimethylcarbonate, dimethyl sulfate, iodomethane, bromomethane, methyl tritiate, methyl benzenesulfonate, trimethyloxonium tetrafluoroborate or methyl fluorosulfonate. In some embodiments, the methylating agent is iodomethane or methyl benzenesulfonate. The organic solvent that may be used for methylation includes for example toluene, xylenes, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, dimethyl sulfoxide (DMSO) and mixtures thereof.

[55] The product mixture containing compound X is transferred to the filter and mixed with a solvent which facilitates enriching the target isomer with the undesired isomer remaining in the mother liquor. Suitable solvents include for example ethyl acetate, propyl acetate, and tetrahydrofuran.

[56] While the formula of compound IX contains an oxylate as the anion, other anions resulting from for example hydrogen chloride, hydrogen bromide, hydrogen iodide, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene- 1 -sulfonic acid, naphthal ene-2- sulfonic acid, and tartaric acid can also be used in place of oxylate.^

[57] Compound IX or its analogs with other anions described above can be prepared by flowing a mixture of compound Villa and an acrylate through a flow reactor to form an acrylated compound. The acrylate is of the formula CH2=CHC0Y, wherein Y is OR¹ or NR²R³, R¹ is Ci-ealkyl (e.g., methyl, ethyl, propyl, tert-butyl, etc.), aryl or heteroaryl, and R² and R³ are the same or different and each is independently selected from hydrogen, Ci-ealkyl, aryl and heteroaryl. In some embodiments, the acrylate is tert-butyl acrylate. The solvent for the acrylation reaction can be for example toluene, xylenes, benzene, ethyl acetate, di chloromethane, and chloroform. In some embodiments, the solvent is toluene.

[58] The acrylation reaction can be quenched with a base, followed by collection of the acrylated compound in the organic phase. The base for quenching or stopping the reaction can be an organic base or inorganic base such as sodium hydroxide, sodium carbonate, potassium hydroxide and potassium carbonate. The compound then reacts with an acid to form a salt which is then collected in a filter. The anion of the salt can be for example chloride, bromide, iodide, methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalene- 1 -sulfonate, naphthal ene-2-sulfonate, and tartarate. In some embodiments, the anion is oxylate.

[59] Compound Villa can be prepared as illustrated below. The process includes flowing a mixture of compound V and phosphorous oxychloride in a flow reactor to form compound VI. The mixture may have a solvent including for example acetonitrile, toluene, xylene and any mixture thereof. Compound VI is neutralized and then reduced to provide compound VII. After isolating an organic phase enriched in racemic tetrahydropapaverine (VII), an S-arylproprionic acid is introduced to selectively crystallize an R-tetrahydropapaverine S-arylproprionic (VIII) salt with an S- tetrahydropapaverine R-arylproprionic salt in solution. The target isomer can be collected in a filter. Subsequent neutralization with a base gives rise to Compound Villa. In some embodiments, the S- arylproprionic acid is naproxen. In other embodiments, the S-arylpropionic acid comprises S- ibuprofen, S-flurbiprofen, S-tropic acid, for example.

[60] Alternatively, compound Villa is made using the following process: The present invention provides a method for preparing a compound of formula (VII), characterized in that the method comprises the step of adding a chiral organic acid to a mixture containing the compound of formula (VII) to form a salt, wherein the chiral organic acid is selected from at least one of D-tartaric acid, D-malic acid, D-aspartic acid, D-glutamic acid, D-mandelic acid, N-acetyl-D-glutamic acid, D- pyroglutamine, D-quinic acid, D-camphorsulfonic acid, D-camphoric acid, and diacetyl-D-tartaric acid.

[61] In some embodiments, adding a salt-forming solvent and a chiral organic acid to the mixture to form a salt, crystallizing, filtering, adding or not adding water to the filter cake, and adding base to adjust pH, extract with an extraction solvent, and remove the solvent from the organic phase to prepare the compound of formula (VII trans); optionally, the method further includes the step of adding a recrystallization solvent to perform recrystallization after the step of removing the solvent from the organic phase.

[62] In some embodiments, the chiral organic acid is selected from at least one of D-tartaric acid, D-malic acid, D-mandelic acid, D-camphoric acid, and diacetyl-D-tartaric acid.

[63] In some embodiments, the salt-forming solvent is selected from alcohols, esters, acetonitrile, and tetrahydrofuran; optionally, the salt-forming solvent is selected from at least one of methanol, ethanol, and isopropanol.

[64] In some embodiments, the extraction solvent is selected from at least one of alcohols, ethers, ketones, esters, alkanes, halogenated alkanes, aromatic hydrocarbons, tetrahydrofuran, and carbon disulfide; optionally, the extraction solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, acetone, butanone, ethyl acetate, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, and carbon disulfide; optionally, the extraction solvent is selected from at least one of ethyl acetate and di chloromethane.

[65] In some embodiments, the recrystallization solvent is selected from at least one of alcohols, ethers, ketones, esters, alkanes, halogenated alkanes, aromatic hydrocarbons, tetrahydrofuran, carbon disulfide, and acetonitrile; optionally, the recrystallization solvent is selected from at least one of methanol, ethanol, isopropanol, petroleum ether, ethyl acetate, n-pentane, cyclohexane, n-octane, n-heptane, n-hexane, acetonitrile, acetone, butanone.

[66] In some embodiments, the ratio of the amount of the chiral organic acid to the substance of the compound of formula (VII) is > 1 : 1; optionally, the ratio of the amount of the chiral organic acid to the substance of the compound of formula (I) is 1:1~ 2:1; the base can comprise an aqueous solution of KOH or NaOH, or both; the pH greater than 7.

[67] In some embodiments, the above preparation method is in the presence of a catalyst, a mixed solution of a compound of formula (VII), formic acid and a reactant A reacts in a reaction solvent to produce a compound of formula (Villa). Separate the organic phase from the reaction liquid. After removing the solvent from the obtained organic phase, add the salt-forming solvent and chiral organic acid to the residue to form a salt, crystallize, filter, add water or no water to the filter cake, add lye to adjust the pH, and extract solvent extraction, remove the solvent from the obtained organic phase, and optionally add a recrystallization solvent to recrystallize to obtain the compound of formula (Villa).

[68] In some embodiments, the mass-volume ratio of the compound of formula (VII) to the salt-forming solvent is 1 :2-30 g/mL, optionally 5-20 g/mL.

[69] In some embodiments, the reactant A is selected from at least one of trimethylamine, triethylamine, and tributylamine; optionally, the reactant A is triethylamine.

[70] In some embodiments, optionally, before the step of separating the organic phase, a quencher is added to the reaction solution of the compound of formula (Villa).

[71] In some embodiments, the compound is a mixed cis/trans solution of a compound of formula (VII), formic acid and triethylamine and reaction in reaction solvent to produce compound of formula (Villa).

[72] In some embodiments, the reaction solvent is selected from alkanes, halogenated alkanes, amides, and sulfoxides, and may be selected from at least one of methylene chloride, DMF, acetonitrile, and DMSO.

[73] In some embodiments, the quencher is selected from at least one of NaOH, KOH, NaHCOs, Na2CO3, KHCO3, K2CO3 and their aqueous solutions.

[74] In some embodiments, the ratio of the compound of the formula (VII) to the reaction solvent is 1 : (2-8) (g/mL).

[75] In some embodiments, the ratio of the compound of formula (VII) to the mixed solution of formic acid and triethylamine is 1 : (1.0 — 5.0) (g/mL). [76] In some embodiments, the formic acid in the mixed solution of formic acid and tri ethylamine: tri ethylamine is 2-3: 1, 5:2(v/v).

[77] In some embodiments, the mass of the catalyst is 0.5% to 5% of the mass of the compound of formula (VII), optionally 0.5% to 2%;

[78] The structure of the catalyst is shown in formula (XIII):

wherein: R is benzene optionally substituted by at least one of Ci-Ce alkyl, Ci-Ce alkoxy, halogen, and hydroxyl, and the benzene ring in R has six coordination sites to coordinately bind to the Ru atom; Ar is an aryl group optionally substituted with at least one of Ci-Ce alkyl, Ci-Ce alkoxy, halogen, and hydroxyl, and optionally, R is benzene optionally substituted with at least one of Ci-Ce alkyl groups.

[79] In some embodiments, R is selected from p-cumyl methane and benzene.

[80] In some embodiments, Ar is selected from phenyl or naphthyl optionally substituted with at least one of Ci-Ce alkyl.

[81] In some embodiments, Ar is selected from 4-methylphenyl, 2,4,6-trimethylphenyl, 1- naphtholyl.

[82] In some embodiments, the catalyst is (S,S)-N-(p-toluenesulfonyl)-l,2- diphenylethanediamine (p-cumene) ruthenium(II) chloride.

[83] In some embodiments, the the method comprises the following steps: to a quantity of (S,S)-N-(p-toluenesulfonyl)-l,2-diphenylethanediamine ( P-cumene)ruthenium(II) chloride, adding the reaction solvent and a mixed solution of formic acid and triethylamine to prepare a ready-to-use solution; dissolving the compound of formula (VII) in the reaction solvent, and then add the ready -to-use solution to the reaction at room temperature; adding a quencher to the reaction solution of the compound of formula (Villa); and allowing the solution to stand for layering or extract solvent extraction; removing the solvent from the organic phase; adding the residue to the salt-forming solvent; adding a chiral organic acid, and reflux with stirring; stirring and cool to crystallize, filter, dissolve the filter cake with water; adding activated carbon and stirring; filtering, and adding alkali to the filtrate to adjust pH > 7; and extracting the filtrate with extraction solvent, and concentrating to dryness, to make the compound of formula (Villa).

[84] In an alternative embodiment, the step of concentrating to dryness further comprises: adding a recrystallization solvent to reflux to dissolve; cooling to crystallize; and filtering and drying to obtain a compound of formula (Villa).

[85] Compound V can be prepared as illustrated below. Flowing a mixture of compound I and compound II through a flow reactor leads to the formation of compound III. Subsequently, a mixture of the compound III and compound IV in the presence of a base is flowed through in a flow reactor to provide compound V, which can be precipitated out in a suitable solvent. In some embodiments, compound V is precipitated out and collected in a filter. In some embodiment, the two flow reactors are connected. In some embodiments, the flow reactor for the formation of compound V and the filter are connected.

[86] Other agents suitable for preparing compound III include for example thionyl chloride, phosphorous trichloride and phosphorous oxychloride. Non-limiting examples of base for formation of compound V include triethylamine, diisopropylethylamine, and pyridine.

[87] One or more solvents may be used for precipitation of compound V. In a system for recrystallization or compound precipitation as described above using two or more solvents, one of the solvents may better solubilize compound V than the other and include for example methanol, ethanol, isopropanol, tetrahydrofuran (THF), acetone, dichloromethane, ethyl acetate and any mixture thereof. The other solvent with poor solubilizing capability includes for example diethyl ether, pentane, n- hexane, n-heptane, cyclohexane, petroleum ether, and the like.

EXAMPLES

[88] Compound III (7V-(2,3-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (cis amide) was prepared as shown below:

[89] 3,4-dimethoxyphenylacetic acid (607.8 g, 3.1 moles, 1 equiv.), N,N- dimethylformamide (96.8 mL) and dichloromethane (1.06 L) were charged to a glass bottle and stirred until homogeneous. The solution was filtered over a bed of celite to afford a 1.6 M solution of 3,4- dimethoxyphenylacetic acid. This solution served as the carboxylic acid feedstock. Oxalyl chloride (511.1 g, 4.03 moles, 1.3 equiv.) and DCM (326 mL) were charged to a glass bottle and stirred until homogeneous. This solution served as the chlorination feedstock.

[90] Two piston pumps, one for each feedstock, were plumbed with PFA tubing (1/8” OD, 1/16” ID) and connected to a T-fitting (IDEX, PEEK, 0.050” bore). The outlet port of the T-fitting was connected inline to the PF or CSTR reactors. A 7.5’ length of PFA tubing (3/16” OD, 1/8” ID) was fitted into three aluminum clam shell reactors (-300” tubing per reactor) and equipped with heating pads and thermocouples for temperature control and temperature monitoring. The reactor tubing was connected in series using union fittings (IDEX, PEEK, 0.050” bore). The reactor outlet was plumbed to a back pressure regulator (BPR, 100 psi) with PFA tubing (1/8” OD, 1/16” ID) and the BPR outlet was plumbed to a collection vessel. The two feedstocks were pumped into the reactors at a total flow rate of 32 mL/min (22 mL/min for carboxylic acid feedstock and 10 mL/min for chlorination feedstock) to achieve a residence time of 5 minutes. The first ten minutes of the continuous run was diverted to waste. The desired acid chloride material was collected into vessel (2.7 L) and characterized by quantitative nuclear magnetic resonance spectroscopy. The collection was >90% 3,4-dimethoxyphenylacetyl chloride (III) and the concentration was determined to be 1.6 M using mesitylene as an internal standard. This material was aged overnight to allow dissolved HC1, CO and CO2 to bubble out of solution and served as acid chloride feedstock.

[91] Homoveratrylamine (562 g, 3.1 moles, 1 equiv.), 7V,7V-diisopropylethylamine (801 g, 6.2 moles, 2 equiv.) and DCM were charged to a glass bottle and stirred until homogeneous. This solution served as the amine feedstock. Isopropanol (1 L) and pentane (4 L) were charged into a bottle. This solution served as the anti-solvent feedstock. The same setup used for the generation of III was used for the synthesis of cis amide. An additional pump was required for the antisolvent, and this solvent was plumbed to the cis amide collection vessel. The PF or CSTR reactors were heated to 40 °C and the two feedstocks were pumped into the reactors at a total flow rate of 18 mL/min (9 mL/min for acid chloride feedstock and 9 mL/min for chlorination feedstock) to achieve a residence time of 10 minutes. The first 20 minutes of the continuous run was diverted to waste. Collection was plumbed to a crystallization vessel and the reactor outlet stream and antisolvent feedstock were pumped into the vessel at an overall flow rate of 36 mL/min. Upon complete consumption of the acid chloride and amine feedstocks, the reactors were flushed with DCM and collection continued for ten minutes. The reactor outlet was diverted to waste and the reactors were flushed for 15 minutes with DCM followed by a 15-minute flush with methanol.

[92] The resulting collection became a dense slurry and the solid was filtered over a glass fritted funnel by vacuum filtration. The resulting solid was washed with 20% IPA in pentane, filtered, slurried in 20% IPA in water and filtered to afford a pale yellow to white solid (677.1 g, liquid chromatography area percent >98%, 61% yield).

[93] Compound VIII (//-tetrahydropapaverine CS')-2-(6-methoxynaphthalen-2-yl)propanoic acid) was prepared according to the following steps:

[94] Cis amide (748.8 g, 2.1 mol, 1 equiv., (Compound III)), phosphorous (V) oxychloride (404.1 g, 2.64 mol, 1.3 equiv.) and 3.5 L ACN were charged into a glass bottle to serve as cis amide feedstock. Potassium hydroxide (1402.5 g, 25 moles, 5 M) was charged to a glass bottle and diluted to 5 L with water to serve as KOH feedstock. Sodium borohydride (750 g, 19.84 moles) and 5 M sodium hydroxide (1.5 L) were combined in a glass bottle and stirred until homogeneous; this solution was diluted with water to 5 L to serve as sodium borohydride feedstock. Methanol, toluene, and water were charged to three different glass bottles (5 L each). Each of these solutions will serve as feedstocks for the process. [95] Unless otherwise noted, milliGAT® piston pumps were used for all feedstocks. A 2.5’ length of PFA tubing (3/16” OD, 1/8” ID) was fitted into an aluminum clam shell reactor and equipped with a heating pad and thermocouple for temperature control and temperature monitoring. The reactor outlet was plumbed to a back pressure regulator (BPR, 100 psi) with PFA tubing (1/8” OD, 1/16” ID) and the BPR outlet was plumbed to a T-fitting. The potassium hydroxide line was plumbed into the same T-fitting and the outlet of the T-fitting was plumbed to a 250 mL gravity separator. For the gravity separator, the upper organic phase tubing was plumbed to a surge tank (herein referred to as the DiHPAP surge tank or DST) and the lower aqueous layer was plumbed to a waste vessel. The DST, methanol and sodium borohydride feedstocks were all plumbed to a continuous stirred tank reactor (CSTR I); a peristaltic pump fitted with Chem-Durance tubing was used for DST. A dip tube was placed at the bottom of the vessel and the outlet of the dip tube was plumbed to a second continuous stirred tank reactor (CSTR II). The toluene and water feedstocks were also plumbed to CSTR II. A dip tube was placed at the bottom of the vessel and the outlet of the dip tube was plumbed to a packed bed of acid washed sand and the packed bed outlet was plumbed to a liquid-liquid membrane separator (equipped with a hydrophobic membrane) where the aqueous phase was plumbed to a waste vessel and the organic phase, containing compound VII, was plumbed to a surge tank (herein referred to as TP surge tank or TPST); a peristaltic pump fitted with Chem-Durance tubing was used to pump CSTR II solution into packed bed and liquid-liquid membrane separator.

[96] The plug flow reactor was heated to 120 °C and flow of cis amide feedstock into the PFR was initiated (7.8 mL/min) to achieve a 7.5-minute residence time. The first 30 minutes of collection was diverted to waste. Next, flow of potassium hydroxide was initiated (15.6 mL/min) and the total flow rate into the gravity separator was 23.4 mL/min. After 200 mL of solution had accumulated in the DST, flow was initiated for the DST (7.8 mL/min), methanol (7.8 mL/min) and sodium borohydride (4.4 mL/min) feedstocks into CSTR I to give a total flow rate of 20 mL/min. When the fill volume reached 1 L, the collection vessel was replaced with an identical vessel. The previously collected material was aged at 60 °C overnight.

[97] Aged CSTR solution was pumped into CSTR II (20 mL/min). At the same time, flow of water (20 mL/min) and toluene (10 mL/min) feedstocks into CSTR II was initiated. When the fill volume reached 200 mL in CSTR II, flow into the packed bed and liquid-liquid membrane separator was initiated. Both the organic and aqueous flows from the membrane separator were diverted to waste for the 30 minutes. After an hour, the aqueous flow remained diverted to waste and the organic phase was collected in the TP surge tank.

[98] The material in the TP surge tank (LCAP purity: 93.2%) was used as a feedstock for the preparation of compound XIII. A solution of (5)-2-(6-methoxynaphthalen-2-yl)propanoic acid) (350 g) was prepared in ethyl acetate (1 L) and served as the CS')-naproxen feedstock. The two solutions were combined into a filter-washer-dryer at flow rates such that a 1 :0.6 TP in toluene feedstock to GS')- naproxen feedstock was achieved. The material was seed with 2 wt. % (A-tetrahydropapaverine GS')- 2-(6-methoxynaphthalen-2-yl)propanoic acid) salt. The material is aged 30 - 50 minutes, filtered and washed with ethyl acetate to afford the desired (A’-tetrahydropapaverine fS')-2-(6-methoxynaphthalen- 2-yl)propanoic acid) salt (30% overall yield, 60% yield of the desired enantiomer, >98% ee).

[99] Alternative method example:

[100] Compound Villa (A’-tetrahydropapaverine can be prepared according to the following steps:

[101] Compound VII (or the neutral species) would be dissolved in a suitable solvent such as DMSO and serve as feedstock for the reaction. A second feedstock comprising formic acid, triethylamine, RuCl[(R,R)-TsDPEN](mesitylene) and DMSO would serve as the reducing agent feedstock. The solutions would be combined in a continuous stirred tank reactor or plug flow reactor and reacted at until complete conversion was observed. Enantiopure VII would then be isolated using antisolvent addition or reactive crystallization using a 5-naproxen or diacetyl tartaric acid.

[ 102] Alternatively, the feedstock containing Compound VII can be combined with a suitable imine reductase for a biocatalytic reduction. A similar isolation strategy could be employed to yield enantiopure VII.

[103] Compound IX was prepared according to the following steps:

[104] A’-tetrahydropapaverine V-acetyl-L-leucinate (496 g), toluene (1.3 L) and 1 M sodium hydroxide (1.5 L) were charged to a glass bottle; another counterion such as (5)-2-(6- methoxynaphthalen-2-yl)propanoic acid could be substituted for V-acetyl-L-leucinate. The mixture was stirred until no solid is observed. The layers were separated by gravity, the organic phase was dried over sodium sulfate and filtered to remove any insoluble material; typical water content was 3000 ppm. This material served as TP feedstock. A 10% (v/v) acetic acid and benzyl acrylate solution was prepared and served as benzyl acrylate feedstock. A 20% IPA in hexanes solution was prepared and served as anti solvent feedstock.

[105] Two piston pumps, one for each feedstock, were plumbed with PFA tubing (1/8” OD, 1/16” ID) and connected to a T-fitting (IDEX, PEEK, 0.050” bore). The outlet port of the T-fitting was connected inline to the reactors. A 68.4’ length of PFA tubing (3/16” OD, 1/8” ID) was fitted into three aluminum clam shell reactors (-300” tubing for two reactors and -224” tubing for the third reactor) and equipped with heating pads and thermocouples for temperature control and temperature monitoring. The reactor tubing was connected in series using union fittings (IDEX, PEEK, 0.050” bore). The reactor outlet was plumbed to a back pressure regulator (BPR, 100 psi) with PFA tubing (1/8” OD, 1/16” ID) and the BPR outlet was plumbed to a collection vessel; a filter-washer-dryer can be used for this unit operation. A third piston pump for the antisolvent feedstock was plumbed directly to the collection vessel.

[106] The TP feedstock (7.53 mL/min) and benzyl acrylate feedstock (0.73 mL/min) feedstock were pumped into the reactors at 130 °C at an overall flow rate of 8.26 mL/min to achieve a residence time of 20 minutes. The first 35 minutes of collection was diverted to waste. When collection began, the flow of the antisolvent feedstock was initiated at a flow rate of 24.8 mL/min. The resulting precipitate was stirred, filtered and washed with isopropanol to give benzyl (R)-3-(l- (3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)propanoate (259.2 g, LCAP purity: >98%). The collection vessel could be a filter-washer-dryer (FWD). A dual FWD setup would allow for fully continuous production of benzyl (A)-3-(l-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4- dihy droi soquinolin-2( 1 H)-yl)propanoate .

[107] Compound X (lA,2A)-2-(3-(benzyloxy)-3-oxopropyl)-l-(3,4-dimethoxybenzyl)-6,7- dimethoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) was prepared according to the following steps:

[108] Benzyl(A)-3-(l-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)- yl) propanoate (20.0 g, 0.0396 mol) was added to a round bottom flask along with 5 equiv. of methyl benzenesulfonate (34.06 g, 0.198 mol) and 4 mL dichloromethane. The reaction was heated in an oil bath at 50 °C with magnetic stirring for 1 hour. The heating was then turned off and 100 mL diethyl ether was added to the reaction and was stirred vigorously for 30 mins. The ether was decanted from an oil, which was then dissolved in 80 mL THF and heated to 50 °C to dissolve the oil. At this point, liquid chromatography area percent values show the solution is composed of 69% of the desired 1R, 2R diastereomer with 21% of the \R, 2S diastereomer, and 8% unreacted starting material. The solution was then cooled to room temperature and 100 mg of seed material (0.5% by weight) was added. Within 20 mins white precipitate had formed. The precipitate was filtered under a cone of nitrogen and washed with 20 mL THF. The resulting solids were transferred to a flask and dissolved in 10 mL DCM and 50 mL ethyl acetate and stirred on ice for 30 min. The resulting bright white solids were filtered and washed with 20 mL cold ethyl acetate and dried, resulting in 5.5 g, (30% yield), 99.85% HPLC purity, with 0.15% of the 1R, 2S diastereomer.

[109] Compound X (lA,2A)-2-(3-(benzyloxy)-3-oxopropyl)-l-(3,4-dimethoxybenzyl)-6,7- dimethoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) can be prepared according to the following steps:

[110] This process is performed by flowing a solution of compound (IX) and methyl benzenesulfonate in THF through a plug flow reactor at 50 °C with a residence time of 1 hour. The reaction stream will be diluted in THF and crystallized to give a crude powder. This powder will be recrystallized in DCMZEthyl acetate to produce purified product.

[111] Compound X (lA,2A)-2-(3-(benzyloxy)-3-oxopropyl)-l-(3,4-dimethoxybenzyl)-6,7- dimethoxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) can be prepared according to the following steps:

[112] Compound IX can be dispensed into a continuous stirred tank reactor at 50 °C (CSTR I) by automated powder dispensing. Methyl benzenesulfonate and THF is also be pumped into CSTR I. A dip tube would be placed in CSTR I and the outlet would be plumbed to a second CSTR at 50 °C. The residence time in CSTR I would be at least 10 minutes and not more than 20 minutes. The residence time in CSTR II would be at least 30 minutes and not more than 75 minutes. A dip tube would be placed in CSTR II, and the outlet plumbed to a crystallization vessel. Feedstocks of THF and an antisolvent would also be pumped into the crystallization vessel. Upon crystallization and subsequent aging of the material, the slurry could be transferred to a filter-washer-dryer for isolation of Compound X.

[113] Compound XI ((lA,2A)-2-(2-carboxyethyl)-l-(3,4-dimethoxybenzyl)-6,7-dimethoxy- 2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) was prepared according to the following steps: [114] ( 1 A,2A)-2-(3 -(benzyloxy)-3 -oxopropyl)- 1 -(3 ,4-dimethoxybenzyl)-6, 7 -dimethoxy-2- methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) (1.0 g, 0.0015 mol) (99.85% HPLC purity, with 0.15% of the 1R, 2S diastereomer) was dissolved in 4 mL absolute ethanol. To this solution was added 0.1 g of 5% Pd/C and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum. The resulting oil was crystallized in an acetone:acetonitrile mixture to produce colorless crystals with an HPLC purity of 98.7%. with .17% of the 1R, 2S diastereomer.

[115] Compound XI ((lA,2A)-2-(2-carboxyethyl)-l-(3,4-dimethoxybenzyl)-6,7-dimethoxy- 2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) can be prepared according to the following steps:

[116] This process is performed by flowing a solution of compound (X) in an alcoholic solvent that has been charged with hydrogen gas through either a packed bed or fluidized bed of 5% Pd/C within a stainless-steel column capped with sintered stainless-steel filter plates. The reaction solution is then concentrated, combined with acetone and acetonitrile, and crystallized at room temperature to produce purified product.

[117] Compound XI ((lA,2A)-2-(2-carboxyethyl)-l-(3,4-dimethoxybenzyl)-6,7-dimethoxy- 2-methyl-l,2,3,4-tetrahydroisoquinolin-2-ium besylate) was prepared according to the following steps:

[118] A Thales Nano H-Cube Mini hydrogenation flow reactor was assembled in accordance with the user manual. Compound X was dissolved in methanol (84 mg/mL) and flowed (3 mL/min) through a 72 x 4 mm 10% Pd/C packed bed reactor with hydrogen system pressure at 1 bar and a column temperature of 60 °C. The collection was analyzed by LC-MS and the crude collection was 88.4 LCAP Compound XI with 5.2 LCAP Compound X remaining. The crude collection was concentrated under reduced pressure to afford a clear, colorless oil. The crude residue was dissolved in acetonitrile and stirred until homogeneous. Acetone (5 V relative to acetonitrile) was added, and the solution was stirred at room temperature for three days. The resulting slurry was filtered to obtain a white solid. The solid washed with acetone and dried under vacuum. The resulting material was >99 LCAP compound XI as analyzed by HPLC and LCMS.

[H9] Compound XII (R,R~ cisatracurium besylate) was prepared according to the following steps: [120] Compound XI (159 g, 270 mmoles, 1 equiv.), benzenesulfonic acid (47.5 g, 300 mmoles, 1.1 equiv.), 1,5-pentanediol (13.5 g, 130 mmoles, 0.48 equiv.) and DCM (220 mL) were charged to a glass bottle. This material served as cis acid feedstock. A packed bed of 3 A molecular sieves (pellets) was used as the dehydrating agent (125 g). The cis acid feedstock was circulated through the drying column continuously for 24 hours at which point LC-MS analysis indicated 76.9% LCAP cisatracurium besylate.

[121] This crude collection can be diluted with DCM and washed with water to afford a solution of pure cisatracurium besylate. Isolation of solid cisatracurium besylate can be achieved with reverse anti-solvent addition (2-methyltetrahydrofuran/toluene), lyophilization or spray drying.

[122] It will be appreciated by persons skilled in the art that the invention described herein is not limited to what has been particularly shown and described. Rather, the scope of the invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific component of the device, or a reagent or intermediate of the reaction, or a step of the method, and may result from a different combination of described component, reagent or intermediate, or step, or that other undescribed alternate embodiments may be available for a device or method, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

[123] CLAIMS

1. A method of preparing a compound of Formula XII, comprising reacting a compound of Formula XI and 1,5-pentanediol in the presence of an acid in a first organic solvent, wherein the first solvent is capable of dissolving the benzenesulfonic acid and 1,5-pentanediol;

and precipitating out the compound of Formula XI with a second solvent.

2. The method of claim 1, wherein the first organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran (THF), acetone, dimethylformamide, dimethylacetamide, 1,2-di chloroethane, dimethylsulfoxide (DMSO), ethyl acetate, dichloromethane, chloroform, acetonitrile, and any mixture thereof.

3. The method of claim 1, wherein the second organic solvent is selected from the group consisting of diethyl ether, diisopropyl ether, tert -butyl methyl ether, toluene, xylenes, and any mixture thereof.

4. The method of claim 1, wherein the acid in the first organic solvent is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid (TFA), methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Amberlyst® 15 hydrogen form, Amberlite® IR120 hydrogen form or Amberjet® 1200 hydrogen form, POCh and SOCh.

5. The method of claim 1, wherein the reaction in the reactor is allowed to proceed at a temperature ranging from about 50 °C and 150 °C.

6. The method of claim 1, wherein the reaction is allowed to continue for about 5 to about 90 minutes.

7. The method of claim 1, further comprising obtaining the compound XI prior to the reaction of claim 1, comprising: flowing a mixture of compound Formula X and an acid through a first reactor to form the compound XI; and

transferring the compound XI to a first filter, wherein the plug flow reactor comprises a solvent selected from dichloromethane or similar solvent, such as, for example, chloroform, or mixtures of propan-2- one/cyclopentane, and ethyl acetate/ethanol, ethyl acetate/heptane, ethyl acetate, MTBE, toluene, 2-MeTHF.

8. The method of claim 6, wherein the first reactor and the first filter are connected for transferring the compound XI.

=2 The method of claim 6, further comprising precipitating out and washing the transferred compound XI. $

10. The method of claim 6, further comprising obtaining the compound X, comprising: neutralizing a compound of IX with a base;

flowing a mixture of the neutralized compound and a methylating agent through a second reactor to form the compound X; and enriching in a second filter the compound X over an undesired diastereomer.

11. The method of claim 9, wherein the second reactor and the second filter are connected for transferring the compound X.

12. The method of claim 9, wherein the methylating agent is iodomethane.

13. The method of claim 9, wherein the mixture of the neutralized compound and the methylating agent is dissolved in a solvent selected from toluene, xylenes, ethyl acetate, dichloromethane, chloroform, acetone, acetonitrile, dimethyl sulfoxide (DMSO) and mixtures thereof and any mixture thereof. The method of claim 9, further comprising obtaining the compound of Formula IX, comprising

flowing a mixture of compound Villa and an acrylate through a third plug flow reactor to form an acrylated compound, wherein the acrylate is of the formula CH2=CHCOY, wherein Y is OR¹ or NR²R³, R¹ is Ci-ealkyl, aryl or heteroaryl, and R² and R³ are the same or different and each is independently selected from hydrogen, Ci-ealkyl, aryl and heteroaryl; mixing the acrylated compound with oxalic acid to form the compound of Formula IX; and isolating the compound of Formula IX in a third filter. The method of claim 13, further comprising adding a base to the mixture after the formation of the acrylated compound. The method of claim 13, wherein the mixture of the compound Villa and the acrylate further comprises a solvent selected from toluene, xylenes, benzene, ethyl acetate, dichloromethane, and chloroform and any mixture thereof, and wherein the acrylate is tert-butyl acrylate. The method of claim 13, further comprising obtaining the compound Villa, comprising:

29

flowing a mixture of compound V and phosphorous in a fourth reactor to form compound VI; reducing the compound VI to compound VII; mixing the compound VII with a S-arylproprionic acid to form compound VIII; isolating the compound VIII in a fourth filter and neutralizing it to form the compound Villa. The method of claim 13, wherein the S-arylproprionic acid is naproxen. The method of claim 13, further comprising obtaining the compound V, comprising:

flowing a mixture of compound I and compound II through a fifth reactor to form compound III in a continuous flow system to form 3,4-dimethoxyphenylacetyl chloride (III)); and flowing a mixture of the compound III and compound IV in the presence of a base in a sixth reactor to form the compound V. The method of claim 18, wherein the compound V is precipitated out in a fifth filter. 30

21. The method of claim 18, wherein the fifth reactor is connected to the sixth reactor and the sixth reactor is connected to the fifth filter.