DESC:Field of Invention
The present invention relates to the field of pharmaceutical chemistry and organic chemistry, specifically a novel process for the synthesis of tapentadol, structurally represented by the compound of formula (1), intermediates and salts thereof.
Background of the Invention
Tapentadol (1), is a central analgesic invented by German pharmaceutical company Grünenthal in the late 1980s and further developed by Johnson & Johnson. It is the first single-molecule drug known to have a dual action mechanism of both the µ-type opioid receptor agonist and norepinephrine reuptake inhibitor. The USFDA first approved of tapentadol on Nov 20, 2008, for the treatment of moderate to severe acute pain.

Several methods are known in the art for the synthesis of tapentadol (1) i.e., 3-((2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl)phenol and salts thereof.
For example, the synthesis described in U.S. Patent No. 6,344,558 starts by the conversion of the tertiary hydroxy group of (2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-3-pentanol in the presence of thionyl chloride to yield its corresponding chloride, and further removal of the chloride by treatment in the presence of zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride with or without triphenylphosphine to yield the intermediate (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride, a precursor of tapentadol (1). A disadvantage of the process is the use of excessive amounts of thionyl chloride which is known to be a corrosive reagent. Furthermore reagents such as zinc borohydride, zinc cyanoborohydride and tin cyanoborohydride do have the potential to present considerable fire and health danger when used on industrial scale. The major disadvantage however is the need to separate the stereoisomers via chiral chromatography which is expensive, time consuming and not suitable for a commercial scale up.
An alternate process for obtaining tapentadol (1) is described in PCT Publication No. WO 2004/108658, wherein (Z,E)-(2R)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethylamine hydrochloride is produced by treating (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol with acid to obtain a mixture of (2R,3R) and (2R,3S)-3-(3-methoxyphenyl)-N,N-2-trimethylpentanamine; further the required stereoisomer is separated and the preferred (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine isomer was treated with concentrated hydrobromic acid to yield tapentadol. The main disadvantage of this process is the separation of the stereoisomers at a very late stage of the process, which leads to a very low overall yield that renders the synthesis disadvantageous for any scale up processes.
An alternate example, PCT Publication No. WO 2008/012047 reports the synthesis of tapentadol, starting by reacting 3-bromoanisole which, via organolithium reagent, is transformed into 1-(3-methoxyphenyl)propan-1-one. A Mannich reaction is carried out on this intermediate which leads to a racemic intermediate which is then subjected to an enantiomeric separation by means of resolution with the chiral (2R,3R)-O,O'-dibenzoyltartaric acid. The resolved enantiomer is then subjected to Grignard reaction with ethyl magnesium bromide and finally the product of this reaction is hydrogenated and subsequently demethylated. During the Grignard reaction, the formation of two diastereoisomers is verified; the removal of the undesired isomer (1S,2R) involves the need for crystallization in conditions which lead to the loss of a high percentage of product.
An alternate process for obtaining an intermediate of tapentadol is described in PCT Publication No. WO 2011/067714 by converting (S)-3-(dimethylamino)-2-methyl-1-(3-nitrophenyl)-propan-1-one to (S)-3-(dimethylamino)-2-methyl-1-(3-aminophenyl)-propan-1-one via reduction in the presence of Sn/HCl as catalyst. This reduction, however, is not suitable for large-scale production. The thus obtained compound is then further transformed into 3-(3-aminophenyl)-1-(dimethylamino)-2-methyl-pentan-3-ol by addition of ethyl magnesium bromide. After separation of the thereby obtained diastereomers, (2R,3R)-3-(3-aminophenyl)-1-(dimethylamino)-2-methyl-pentan-3-ol is converted in a three-step process that involves the use of (CF3CO2)2O to yield (2R,3R)-dimethyl-[2-methyl-3-(3-amino-phenyl)-pentyl]-amine. The desired product tapentadol is finally obtained by a final treatment with NaNO2 in the presence of sulfuric acid/water. The drawback of this process is the use of toxic, corrosive and expensive reagents like Sn/HCl and (CF3CO2)2O.
An alternative process for obtaining tapentadol is described in PCT Publication No. WO 2011/080736, wherein 3-methoxyphenylpropan-1-one is converted to 3-(3-methoxyphenyl)-N,N,2-trimethylpent-2-enamide via reaction with bis(ethyl)-1-(dimethylamino)-1-oxopropan-2ylphosphonate in the presence of a base. The resulting compound is obtained as a mixture of E- and Z-isomers in a ratio of 28:72. This compound is further transformed into (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide in an asymmetric hydrogenation step using a Ru based chiral catalyst to give (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide in >89% ee. This compound is then reduced and deprotected to give tapentadol (1). The major disadvantage is the use of Ru catalyst which is an expensive precious metal and expensive chiral ligands, thus rendering the process unviable at commercial scale.
An alternative process described in PCT Publication No. WO 2013/090161 is the synthesis of a salt of tapentadol comprising reacting (E)-3-(3-hydroxyphenyl)acrylic acid with benzyl bromide to obtain (E)-3-(3-(benzyloxy)phenyl) acrylic acid and reduction to (E)-3-(3-(benzyloxy) phenyl) prop-2-en-1-ol. (E)-3-(3-(benzyloxy) phenyl) prop-2-en-1-ol reacts with allyl bromide followed by isomerization in the presence of an organometallic catalyst to yield 1-(benzyloxy)-3-((E)-3-((E)-prop-1-enyloxy)prop-1-enyl)benzene which in turn condenses with 4-(dimethylamino)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)picolinamide in the presence of an organometallic catalyst to obtain (2R,3R)-3-(3- (benzyloxy)phenyl)-2-methylpent-4-enal which is further converted into (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine. This enamine is reacted with an acid to obtain a salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine; finally the salt of (2R,3R)-3-(3-(benzyloxy)phenyl)-N,N,2-trimethylpent-4-en-1-amine is subjected to hydrogenation to obtain the salt of tapentadol. This process however involves the use of expensive chiral ligands which renders it commercially not feasible.
Alternatively, PCT Publication No. WO 2012/103799 provides compounds (2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide, the process for synthesis of the same and its use as intermediates in the process for obtaining tapentadol. The method involves reacting 3-(3-hydroxy protected)phenyl acrylic acid or an alternative trans-pent-2-enoic acid with a chiral auxiliary group in the presence of a carboxylic acid activating agent, the product was further subjected to asymmetric Michael addition with ethyl magnesium halide or the alternative 3-hydroxy protected phenyl magnesium halide in the presence of organic metal reagent in an inert solvent; the resultant product was a-methylated in the presence of alkylating reagent, a strong base or Lewis acid to yield the intermediate that was further subjected to reactions such as removing the chiral auxiliary residue, amidation, reduction of amide carbonyl, removal of phenolic hydroxy protecting group to yield tapentadol and finally the formation of its salt in the presence of an acid. This process appears to yield a relatively pure compound. However, at commercial scale it leads low yields. The process also includes very elaborate setup and a number of reaction steps wherein the number of impurities increase and thus resulted in reduced yield.
The various methods of synthesis for tapentadol (1) disclosed above hold interesting features, however all the methods described have major drawbacks with purity, safety and cost effective concerns that hinder the progress towards bulk production. The processes, majorly adopt to resolution methods such as column chromatography or chiral separation to obtain the enantiomeric pure form of tapentadol (1), leading to high cost and low yield, and are not suitable for industrial scale production. Hence there is a need for a cost effective advantageous synthetic process which is suitable on a commercial scale.
In order to overcome the disadvantages of high cost, low yield and low purity, in the methods for preparation of tapentadol in the prior art, the present invention provides the use of substituted 2-oxazolidinone intermediates in the synthesis of tapentadol (1) and pharmaceutically acceptable salt thereof as an economic, environmental sustainable and convenient process with high chiral purity.
Object of Invention
An object of the invention is to provide an industrially viable, novel process for the preparation of highly enantiomerically pure tapentadol (1), intermediates and salts thereof; using a more sustainable approach that includes fewer reaction steps, easily obtainable and inexpensive raw materials, mild reaction conditions, simple and easy operations, which is economic and environmental friendly with improved yields, high chiral purity and a commercially viable approach. With an added advantage of recovery of material such as substituted 2-oxazolidinone moiety that may be reused during the synthetic process, thus making it economical and sustainable green chemistry.
Summary of the Invention
The present invention provides a novel process making the use of substituted 2-oxazolidinone intermediates in the synthesis of tapentadol and pharmaceutically acceptable salt thereof, rendering it economical and convenient process with high chiral purity.
An embodiment of the present invention provides a novel process for the preparation of a compound of formula (1), wherein the process comprises condensing a compound of formula (8) and (R)-4-substituted-3-propionyloxazolidin-2-one, represented by a compound of formula (7) to form a compound of formula (6).
In the present disclosure, the novel process for the preparation of a compound of formula (1) comprises condensation of compound of formula (8) with a (R)-4-substituted-3-propionyloxazolidin-2-one compound of formula (7) in the presence of a suitable base and a suitable solvent to yield enantiomerically pure compound of formula (6), which further reacts with dimethylamine in the presence of a suitable solvent to substitute the substituted 2-oxazolidone moiety to yield an enantiomerically pure compound of formula (5).
The compound of formula (5) is reduced in the presence of a reducing agent to compound of formula (4) which further undergoes reductive elimination of the hydroxyl group in the presence of a suitable reducing agent, a suitable solvent and a suitable acid to yield a compound of formula (3). O-demethylation of compound of formula (3) in the presence of a suitable acid yields the hydrobromide salt of tapentadol (2), followed by conversion to tapentadol free base (1) and further reacting with hydrochloric acid to yield hydrochloric salt of tapentadol (1a).
Another embodiment of the present invention comprises of recovery of substituted 2-oxazolidone moiety in high enantiomeric purity and yield which may optionally be recycled in the synthesis of compound of formula (7).
An embodiment of the present invention provides novel compounds used as intermediates in the preparation of compound of formula (1), wherein the novel intermediates are structurally represented as follows:
Wherein R may be selected from a substituted or unsubstituted, chained or branched alkyl; substituted or unsubstituted aryl or a hydroxy protecting group (PG) and R' may be selected from a substituted or unsubstituted, chained or branched alkyl; or substituted or unsubstituted aryl.
Another embodiment of the present invention provides a process for salt formation to yield salts of tapentadol; wherein the process comprises of contacting the pure free base of tapentadol (1), with a suitable acid and a suitable solvent at room temperature or any other methods known to a person skilled in the art.
Detailed Description of the Invention
This invention may be understood even more readily by reference to the following detailed description of embodiments of the invention and the examples included therein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described as below.
Definition of Terms
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. It is also to be understood that the terminology used herein is for the purpose of describing the embodiments and is not intended to be limiting.
As used herein, the term "Tapentadol" refers to the chemical compound represented by a compound of Formula 1:

In some embodiments, Tapentadol is referred to as the "free base" meaning that compound is able to accept one proton or donate one pair of electrons. In other words, the amine group is not protonated.
As used herein, the term "comprising" is intended to mean that the processes and methods include the recited elements, but not excluding others. Embodiments defined by each of these transition terms are within the scope of this invention.
As used herein, the term "contacting" refers to bringing two or more chemical molecules to close proximity so that a reaction between two or more chemical molecules can occur. Contacting may be done by fully or partially dissolving or suspending two or more chemicals in one or more solvents, mixing of a chemical in a solvent with another chemical in solid and/or gas phase or being attached on a solid support, such as a resin, or mixing two or more chemicals in gas or solid phase and/or on a solid support, that are generally known to those skilled in the art.
As used herein, the term "reaction conditions" refers to the details under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, pressure, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, hydroxy group protecting conditions, condensation conditions, amination conditions, O-demethylation conditions, reduction conditions, deprotecting conditions, salt forming conditions, etc. Reaction conditions for known reactions are generally known to those skilled in the art.
As used herein, the term "substituent(s)" or “substituted” refers to selection of a moiety from a set of chemical functional groups that ‘may be replaced by’ (or) ‘may take the place of’ a group at a certain position of a molecule such as an alkyl or aryl. Examples include, but are not limited to, one or more of the following: chained or branched alkyl, alkoxy, aryl, aryloxy, halogens, nitro, amines, amides, alcohols, esters, ethers, carboxylic acids, heterocyclic rings etc.
As used herein, the term "solvent" refers to a liquid that dissolves or dilutes a solid, liquid, or gaseous solute to form a solution. Common solvents are well known in the art and include but are not limited to, water; saturated aliphatic hydrocarbons, such as pentanes, hexanes, heptanes, and other light petroleum; aromatic hydrocarbons, such as benzene, toluene, xylene, etc.; halogenated hydrocarbons, such as dichloromethane (DCM), chloroform (CHCl3), carbon tetrachloride (CCl4¬), etc.; aliphatic alcohols, such as methanol (CH3OH), ethanol (C2H5OH), propanol (C3H7OH), isopropyl alcohol (IPA)-((CH3)2CHOH) etc.; ethers, such as diethyl ether, dipropyl ether, dibutyl ether, diisopropylether (DIPE), tetrahydrofuran (THF), dioxane, etc.; ketones, such as acetone, ethyl methyl ketone, etc.; esters, such as methyl acetate (MeOAc), ethyl acetate (EtOAc), etc.; nitrogen-containing solvents, such as dimethylacetamide (DMA), formamide, N,N-dimethylformamide (DMF), acetonitrile (CH3CN), pyridine, N-methylpyrrolidone (NMP), quinoline, nitrobenzene, etc.; sulfur-containing solvents, such as carbon disulfide, dimethyl sulfoxide, sulfolane, etc.; phosphorus-containing solvents, such as hexamethylphosphoric triamide, etc. The term solvent includes a combination of two or more solvents unless clearly indicated otherwise. A particular choice of a suitable solvent will depend on many factors such as including the nature of the solvent and the solute to be dissolved or diluted, nature of the chemical reactions, the intended purpose, etc.
As used herein, the term "acid" is intended to refer to a chemical species that can either donate a proton or accept a pair of electrons from another species. Examples of acids include organic acids, such as carboxylic acids (e.g., maleic acid, lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, etc.); mineral acids (e.g. hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr); and Lewis acids. The term "Lewis acid" used herein refers to an electron deficient species that is capable of accepting a pair of electrons. Examples of Lewis acids that can be used in the present invention are cations of metals and their complexes, where such metals include boron, magnesium, calcium, aluminum, zinc, titanium, chromium, copper, tin, mercury, iron, manganese, cadmium, gallium and barium; the present invention preferably uses boron trifluoride (BF3), boron trifluoride etherate (BF3.Et2O), hydrobromic acid and hydrochloric acid.
As used herein, the term "base" generally refers to chemical compounds that can accept hydrogen ions or donate a pair of electrons. The term "inorganic base" refers to an inorganic compound that can act as a base, such as alkali metal hydroxides, bicarbonates and carbonates. Examples of inorganic base include, but are not limited to, sodium hydride (NaH), sodium carbonate (Na2CO3), potassium hydroxide (KOH), lithium hydroxide (LiOH), barium hydroxide (Ba(OH)2), cesium hydroxide (CsOH), sodium hydroxide (NaOH), sodium bicarbonate (NaHCO3), calcium hydroxide (Ca(OH)2), and magnesium hydroxide (Mg(OH)2). The term "organic base" refers to an organic compound that can act as a base. Examples of organic base include, but are not limited to, triethylamine (TEA), pyridine, potassium tert-butoxide (t-BuOK), lithium diisopropylamide (LDA) etc.
As used herein, the term "reducing agent" also known as "reductant" or "reducer" generally refers to chemical compounds that can lose (or "donate") an electron to another chemical species in a redox chemical reaction. Examples include, but are not limited to a single or a combination of hydrogen, sodium borohydride (NaBH4), lithium aluminiumhydride (LiAlH4), trialkylsilanes such as triethylsilane (TES), vitride (sodium bis(2-methoxyethoxy)aluminiumhydride–(NaAlH2(OCH2CH2OCH3)), sodium amalgam (Na(Hg)), Lindlar catalyst, sodium-aluminium alloy (Na/Al), Zinc amalgam (Zn(Hg)), iron(II) sulfate (FeSO4), tin(II) chloride (SnCl2), diisobutylaluminium hydride (DIBAL-H), hydrogen gas in the presence of transition metals like palladium (Pd), platinum (Pt), etc.
As used herein, the term "crude product" or "crude material" refers to the product/material obtained from a process without or before the purification step and may contain the desired product alone, or together with starting material, reagents, solvents, byproducts from side reactions, moisture, and/or a variety of other impurities. This crude material/product may be wet or dry and obtained as a residue, oil, gummy solid, solid cake, or used in-situ during the synthetic process.
As used herein, the terms "salt formation conditions" or "salt forming conditions" generally refers to conditions used to form a salt between, for example, a compound having a basic group, such as an amine with an organic or inorganic acid. Salt forming conditions may include mixing the molecule having the basic group and the acid in a solvent or a mixture of solvents for a period of time under a certain temperature, which would be generally known to a person skilled in the art. Alternatively, the compound can be passed over an ion exchange resin to form the desired salt or one salt form of the product can be converted into another using the same general process. Salt forming conditions may also be conditions where the acid is a by-product of a reaction forming the compound whose salt is formed.
As used herein, the terms “protecting group” or “PG” refers to a compound that is used to mask a functionality during a process step in which it would otherwise react, which is undesirable. The protecting group prevents the undesirable reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” or "deprotecting" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry [See e.g. Greene’s Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, 4th Edition; John Wiley & Sons, New York (2007)]. The hydroxy protecting group (PG) may be selected and not limited to functional groups such as ethers which comprise of alkyl ethers (wherein the alkyl may be branched or straight chain alkyls) such as methyl ethers, t-butyl ethers, methoxymethyl ether, allyl ether; aryl ethers (wherein the aryls may be unsubstituted or substituted aryls), benzyl ethers; heterocyclic ethers such as tetrahydropyranyl ether; silyl ethers such as t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether etc.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is derived from a variety of physiologically acceptable organic and inorganic acids, when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloric, sulfuric, phosphoric, nitric, hydrobromic, tartaric, acetic, maleic, fumaric, succinic, citric, lactic, palmitic, salicylic, stearic, methanesulfonic, p-toluenesulfonic, and oxalic and the like. Suitable pharmaceutically acceptable salts also include those listed in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985) and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
As used herein, the term “medicament” refers to a pharmaceutical composition containing the compounds prepared by the present invention, wherein the pharmaceutical composition may be used for human or non-human therapy of various diseases or disorders in a therapeutically effective dose.
Surprisingly the present inventors have found that the process according to the present invention for the synthesis of tapentadol (1) is advantageous and in particular cost effective with high enantiomeric and diastereomeric yields, the preparation of a compound of formula (1) will hereinafter be elaborated and identified as Scheme 1. The method according to the present invention processed by introducing a chiral compound of formula (7) in the first step of the synthesis which involves condensation with a cinnamic acid derivative with concomitant generation of two adjacent chiral centers, followed by substitution with dimethylamine and subsequent recovery of the chiral auxiliary group. The use of substituted 2-oxazolidinone intermediates also ensures the purity and high yield owing to the solid formation property of oxazolidinone that eases the process of isolation during synthesis. The final steps involve reduction, deprotection of O-protecting group and formation of a salt.
In a first embodiment, the present invention provides a novel process for the synthesis of compound of formula (1), wherein the process is as described in Scheme 1.

According to Scheme 1, a novel process for the preparation of a compound of formula (1) comprises condensation of compound of formula (8) with (R)-4-substituted-3-propionyloxazolidin-2-one compound of formula (7) to yield enantiomerically pure compound of formula (6) in high yield. Wherein R may be selected from a substituted or unsubstituted, chained or branched alkyl; substituted or unsubstituted aryl or a hydroxy protecting group (PG). R' may be selected from a substituted or unsubstituted, chained or branched alkyl; or substituted or unsubstituted aryl. An alkyl group may include without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and the like. An aryl group may include without limitation, phenyl, benzyl, phenethyl. A hydroxy protecting group include without limitation, acyl groups such as acetyl, propionyl, pivaloyl, benzoyl; ethers such as alkyl ethers (methyl ethers, t-butyl ethers, methoxymethyl ether, allyl ether), aryl ethers (benzyl ether), heterocyclic ethers such as tetrahydropyranyl ether; silyl ethers such as t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether etc. Preferably R is methyl and R' is phenyl or benzyl.
The reaction advances in the presence of a strong base such as sodium hydride (NaH), lithium diisopropylamide (LDA), potassium tert-butoxide (t-BuOK) and the like and a suitable solvent or combination of solvents preferably selected from THF, toluene and the like. The reaction condition is that of condensation conditions with temperature ranging over -65° to 10°C. Optionally the final crude product may be recrystallized in the presence of a solvent preferably isopropyl alcohol (IPA).
In a second embodiment, the novel process for the preparation of a compound of formula (1) comprises of the formation of compound of formula (6) in high enantiomeric purity and yield. It may be isolated or used in-situ in the progress of the reaction.
In a third embodiment, the present invention provides a novel process for preparing compound of formula (5), wherein the compound of formula (6) is reacted with dimethylamine to yield compound of formula (5) in high enantiomeric purity and yield. The reaction advances at 5° to 10°C in a suitable solvent or combination of solvents. Solvents used in the process may preferably be selected from DCM, toluene, and the like.
In a fourth embodiment, the present invention provides a novel process for the preparation of a compound of formula (5), with the release of chiral auxiliary, the substituted 2-oxazolidone moiety that may be recovered as a high enantiomeric pure compound and may subsequently be recycled in the synthesis of compound of formula (7).
In a fifth embodiment, the present invention provides a novel process for the preparation of a compound of formula (4), wherein the process comprises of reducing the compound of formula (5) in the presence of a suitable reducing agent to yield compound of formula (4) in high enantiomeric purity. The reaction advances under reduction conditions in the presence of a suitable reducing agent such as vitride, LiAlH4, NaBH4, and the like; preferably vitride, and a suitable solvent or combination of solvents, preferably selected from THF, toluene and the like; with temperature ranging over -5°C to room temperature (RT).
In a sixth embodiment, the present invention provides a novel process for the preparation of a compound of formula (3), wherein the process comprises reductive elimination of hydroxyl group of compound of formula (4) to yield compound of formula (3) in high enantiomeric purity. The reaction advances under reduction conditions at elevated temperature preferably ranging from RT to 90°C, in the presence of a suitable reducing agent such as trialkylsilane, borohydrides, and the like and optionally in combination with a suitable acid such as a Lewis acid (AlCl3, BF3.Et2O etc.,); preferably selected as a combination of triethylsilane (TES) and BF3.Et2O; and a suitable solvent or combination of solvents preferably selected from acetonitrile, DCM, and the like.
In a seventh embodiment, the present invention provides a novel process for the preparation of a compound of formula (2), wherein the process comprises of O-demethylation to cleave phenolic methyl ether of compound of formula (3) to yield the hydrobromide salt of tapentadol represented by the compound of formula (2) in high enantiomeric purity. The reaction advances in the presence of a suitable acid such as a strong protic acids preferably hydrobromic acid (HBr) and the like; or a Lewis acid such as borontribromide (BBr3) or a thiol and a Lewis acid-thiourea pair such as dodecanethiol and aluminium chloride; optionally a suitable solvent or a combination of solvents may be used to assist the progress of the reaction, the solvent may preferably be selected from acetone, DCM, and the like.
In some embodiments, where R is other than methyl, deprotection may be carried out using one or more organic acids such as acetic acid, trifluoroacetic acid, methanesulphonic acid, p-toluenesulfonic acid and the like, one or more inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like.
In an eighth embodiment, the present invention provides a novel process for the preparation of a compound of formula (1), wherein the process comprises of conversion of compound of formula (2) to a hydrogen chloride salt of tapentadol represented by the compound of formula (1a) via tapentadol free base (1) which may optionally be isolated, purified or used in-situ as a crude product. The reaction advances in the presence of a suitable base preferably sodium hydroxide, a suitable acid preferably hydrochloric acid and optionally a suitable solvent or a combination of solvents may be used to assist the progress of the reaction, the solvent may preferably be selected from acetone, DIPE, DCM, water and the like.
In one preferred embodiment, the novel process of the present invention may be described as given in Scheme 2:

In one embodiment, all the intermediates formed according to the novel process of present invention may be isolated and purified via recrystallization or other methods known in the art.
In an alternative embodiment, all the intermediates formed according to the novel process of present invention may be used in-situ as a crude product without being isolated in the novel process for the preparation of a compound of formula (1).
In another embodiment, the present invention provides novel intermediates used in the preparation of compound of formula (1), wherein the novel intermediates are structurally represented as follows:
Wherein R and R' is defined as hereinbefore.
In another embodiment, the present invention provides a process for the preparation of the salt form of Tapentadol free base, wherein the process comprises of use of the above intermediates in high enantiomeric purity and yields.
Another embodiment of the present invention provides a process for salt formation to yield salts of tapentadol; wherein the process comprises of contacting the pure free base of tapentadol (1), with a suitable acid and a suitable solvent at RT or any other methods known to a person skilled in the art.
Another embodiment of the present invention provides a process for the preparation of a compound of formula (1), wherein the process comprises of formation of tapentadol (1) as free base, optionally isolating, purifying and further conversion to the hydrochloric salt of tapentadol (1a).
An alternative embodiment of the present invention provides a process for the preparation of a compound of formula (1), wherein the process comprises of formation of tapentadol (1) as free base in-situ and further conversion to the hydrochloric salt of tapentadol (1a).
According to the present invention, the industrially viable process yields a stable crystalline/amorphous tapentadol (1) as such or by converting the crude compound obtainable from the said process to a stable crystalline/amorphous form by techniques known in the art.
In an additional embodiment, the present invention provides a novel process for the preparation of a compound of formula (1), comprising the use of starting materials, (E)-methyl 3-((3-substituted)phenyl)acrylate represented by compound of formula (8) and (R)-4-substituted-3-propionyloxazolidin-2-one represented by compound of formula (7), which may optionally may be synthesized according to methods known in the art.
The inventors of the present invention contemplate that this route of synthesis for preparing tapentadol (1) provides improved yields at every stage. It was surprising to find that the described process for the preparation of tapentadol (1) possessed a more sustainable approach with an easily operational, mild reaction conditions, high enantiomeric purity and feasibility on commercial scale.
Further, the present invention been illustrated in the Scheme 1 and Scheme 2 and the following specific and non-limiting examples for functioning need to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Experimental Procedures:
Example 1: Preparation of methyl (3R,4R)-3-(3-methoxyphenyl)-4-methyl-5-oxo-5-((R)-2-oxo-4-phenyloxazolidin-3-yl)pentanoate:
To a suspension of NaH (0.548 mol, 20.23 g, 65% dispersion in oil) in anhydrous THF (1000 mL) under nitrogen atmosphere at 0-5°C, was added drop-wise a solution of (R)-4-phenyl-3-propionyloxazolidin-2-one (0.4566 mol, 100 g) in THF (1000 mL) and the RM was stirred at 10°C for 2 h. The resultant reaction mixture was cooled to -10°C and a solution of methyl-(E)-3-(3-methoxyphenyl)acrylate (0.5022 mol, 96.4 g) in THF (500 mL) was added and stirred at -10°C for 16h. The reaction mixture was further quenched with isopropanol, till the evolution of H2 gas ceased. The reaction mixture was quenched again with 20% NH4Cl solution (500 mL) and solvent evaporated under vacuum. To the resulting residue, DCM (1000 mL) was added and the reaction mixture was washed with saturated NaCl solution (500 mL). The organic layer was separated, dried over anhydrous Na2SO4 and the solvent evaporated under vacuum to obtain the title compound as crude product (173 g, 92%); HPLC analysis indicated 98% de. The crude product was further recrystallized in IPA to yield a solid crystalline product (165 g, 88%).

Example 2: Preparation of methyl (3R,4R)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl-5-oxopentanoate:
A solution of methyl (3R,4R)-3-(3-methoxyphenyl)-4-methyl-5-oxo-5-((R)-2-oxo-4-phenyloxazolidin-3-yl)pentanoate (0.3893 mol, 160 g) in methanol (500 mL) precooled to 5-10°C, was charged 40% dimethylamine aq. solution (0.4670 mol, 150 mL). The reaction mixture was stirred at 5-10°C for 6 h. The reaction mixture was diluted with H2O (250 mL) and stirred at RT for 2 h. The precipitated (R)-4-phenyloxazolidin-2-one was recovered (60 g, 95%). Chiral HPLC indicated >99% ee. The filtrate was concentrated under vacuum and aq. layer was extracted with DCM (3x200 mL). The organic layer was washed with saturated NaCl solution and dried over anhydrous Na2SO4 and solvent was evaporated under vacuum to obtain the title compound as a white solid (108 g, 95%). HPLC purity 93%.

Example 3: Preparation of (3R,4R)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl pentan-1-ol:
A solution of methyl (3R,4R)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl-5-oxopentanoate (5) (0.3413 mol, 100 g) in tetrahydrofuran (500 mL) is cooled to 5-10°C. A 70% solution of vitride (1.3652 mol, 395 mL) was slowly added below RT. After the addition the solution was refluxed for 12 h. The reaction mixture was cooled to 0°C and excess reagent was decomposed with 10% aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with toluene (3x150 mL). The combined organic layers were dried over anhydrous Na2SO4 and distilled under vacuum to obtain the title compound as a crude product (84 g, 98%).

Example 4: Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N-2-trimethylpentan-1-amine:
To a solution of (3R,4R)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl pentan-1-ol (0.3187 mol, 80 g) in CH3CN (400 mL), TES (0.6896 mol, 80 g) was added at RT and stirred for 2 h. To the reaction mixture, BF3.Et2O (0.5634 mol, 80 g) was added slowly drop-wise, temperature increased to 60°C owing to the exothermic nature of the reaction. The reaction mixture was refluxed for 4 h and cooled to RT. Solvent was evaporated under vacuum to obtain a residue to which DCM (400 mL) was added and further treated with 20% aq. KOH solution (200 mL) for 6 h. The organic layer was separated, washed with H2O, dried over anhydrous Na2SO4 and solvent distilled under vacuum to obtain the title compound as a crude product (68 g, 91%).

Example 5: Preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrobromide:
To (2R,3R)-3-(3-methoxyphenyl)-N,N-2-trimethylpentan-1-amine (0.2766 mol, 65 g), 33% HBr in acetic acid (170 mL) was added, stirred for 8 h at RT. The acetic acid was distilled off under vacuum to yield the title compound as crude product (82.7 g, 99%).

Example 6: Preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride:
To 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrobromide (0.2531 mol, 80 g), a precooled solution of NaOH (0.5 mol, 20 g) in H2O (480 mL) was added in several portions and stirred at RT for 2 h. The reaction mixture was concentrated to 160 mL under vacuum. The reaction mixture was cooled to 5-10°C and a mixture of acetone (100 mL) and conc. HCl (50 mL) was added. The reaction mixture was stirred for 2 h at 5-10°C. The resultant precipitate was filtered and washed with a little fresh acetone and dried in the oven at 50°C for 2 h to yield the title compound as a white crystalline solid (62 g, 87%). HPLC purity was >99% and de indicated 99.2%.

An embodiment of the present invention also relates to compositions comprising of compound with formula (1) or methods of the preparations thereof in dosage form of tablets, capsules, suspensions and injections.
Without being limited by theory, the process according to the present invention may be advantageously used to prepare the complex compounds similar to tapentadol (1). The proposed routes of the drug described in the above mentioned schemes are such that it prevents the disadvantages of the prior art. It is envisaged that by providing the alternative routes of synthesis of compounds or related compounds or intermediates of the present invention, the shelf life or stability of the product is enhanced and the impurity content of the product is decreased or rather controlled during the preparation of intermediates, thereby contributing to the overall efficacy of the product.
The proposed process according to the reaction schemes of the present invention are convenient to use by the end users and eliminates high ratio of impurities. Furthermore, the proposed routes of the present invention for the preparation of tapentadol (1) reduces the medication cost due to reduction of steps in final preparation of compound of formula 1, is economic for the end user, reduces drug waste, minimizes hospital and industrial waste and eliminates risk of toxicity by producing in higher purity of compounds.
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.
The invention having been disclosed in connection with the foregoing embodiments, additional variations will now be apparent to persons skilled in the art. Various modifications and variations to the above described in the schemes can be made without departing from the scope of the invention.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the description and synthetic schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
,CLAIMS:1. A process for preparing 3-((2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl)phenol represented by a compound of formula (1) or pharmaceutically acceptable salts thereof, comprising:
(a) Reacting a compound of formula (4) with a suitable reducing agent to form a compound of formula (3) by reductive elimination of hydroxy group;

(b) Deprotecting the compound of formula (3) to form compound of formula (1);

(c) Optionally converting the compound of formula (1) to pharmaceutically acceptable salts thereof by treating with an acid.
2. A process as claimed in claim 1, wherein R represents substituted or unsubstituted, chained or branched alkyl; substituted or unsubstituted aryl or a hydroxy protecting group.
3. A process as claimed in claim 1, wherein a suitable reducing agent in step (a) includes without limitation, trialkylsilanes, borohydrides, and the like; used optionally in combination with a Lewis acid; deprotection is carried out using organic acids such as acetic acid, trifluoroacetic acid, methanesulphonic acid, p-toluenesulfonic acid and the like; inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like.
4. A process for preparing a compound of formula (4), comprising:
(a) Condensing a compound of formula (8) with a compound of formula (7) to yield a compound of formula (6);

Wherein R represents substituted or unsubstituted, chained or branched alkyl; substituted or unsubstituted aryl or a hydroxy protecting group; and R' represents substituted or unsubstituted, chained or branched alkyl; or substituted or unsubstituted aryl,
(b) Reacting the compound of formula (6) with dimethylamine to yield a compound of formula (5);

Wherein R and R' are as defined above,
(c) Subjecting the compound of formula (5) to reduction using a suitable reducing agent to yield a compound of formula (4);

5. A process as claimed in claim 4, wherein step (a) is performed in the presence of a base including without limitation, sodium hydride, lithium diisopropylamide, potassium tert-butoxide and the like; suitable reducing agent in step (c) includes without limitation, vitride, lithium aluminium hydride, sodium borohydride and the like.
6. A process as claimed in preceding claims, wherein solvent(s) are selected from acetone, acetonitrile, dichloromethane, diisopropylether, ethanol, methanol, tetrahydrofuran, toluene, water and the like.
7. A process for preparing 3-((2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl)phenol represented by a compound of formula (1), comprising:
(a) Condensing a compound of formula (8) with a compound of formula (7) to yield a compound of formula (6);

Wherein R' represents substituted or unsubstituted, chained or branched alkyl; or substituted or unsubstituted aryl,
(b) Reacting the compound of formula (6) with dimethylamine to yield a compound of formula (5);

Wherein R' is defined as above,
(c) Subjecting the compound of formula (5) to reduction using a suitable reducing agent to yield a compound of formula (4);

(d) Reacting a compound of formula (4) with a suitable reducing agent to form a compound of formula (3) by reductive elimination of hydroxy group;

(e) Deprotecting the compound of formula (3) to form compound of formula (2);

(f) Treating the compound of formula (2) with a base to yield 3-((2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl)phenol, compound (1).

8. Compounds of formula (4), (5) and (6);

Wherein R represents substituted or unsubstituted, chained or branched alkyl; substituted or unsubstituted aryl or a hydroxy protecting group; and R' represents substituted or unsubstituted, chained or branched alkyl; or substituted or unsubstituted aryl.